MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Immunological Reviews' source. Thu, 18 Mar 2010 13:39:24 +0100 http://www.medworm.com/index.php?rid=3296061&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00888.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296061 Tue, 23 Feb 2010 14:32:01 +0100 3296061 http://www.medworm.com/index.php?rid=3296084&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00882.x Summary: Different dendritic cell (DC) subsets have distinct specialized functions contributed in part by their differential expression of pattern recognition receptors (PRRs). C-type lectin receptors (CLRs) are a group of PRRs expressed by DCs and other myeloid cells that can recognize endogenous ligands as well as a wide range of exogenous structures present on pathogens. Dual roles in homeostasis and immunity have been demonstrated for some members of this receptor family. Largely due to their endocytic ability and subset specific expression, DC-expressed CLRs have been the focus of significant antigen-targeting studies. A number of CLRs function on the basis of signaling via association with immunoreceptor tyrosine-based activation motif (ITAM)-containing adapter proteins. Others conta... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296084 Mon, 22 Feb 2010 00:00:00 +0100 3296084 http://www.medworm.com/index.php?rid=3296083&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00887.x Summary: Since their discovery in 1973, dendritic cells (DCs) have gained strong interest from immunologists because of their unique capacity to sensitize naive T cells. There is now strong evidence that cells of the dendritic family not only control immunity but also regulate responses to self and non-self, thereby avoiding immunopathology. These two complementary functions are critical to ensure the integrity of the organism in an environment full of antigens. How DCs display these opposite functions is still intriguing. Here, we review the role of DC subsets in the regulation of T-helper responses in vivo. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296083 Mon, 22 Feb 2010 00:00:00 +0100 3296083 http://www.medworm.com/index.php?rid=3296082&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00880.x Summary: Each microenvironment is controlled by a specific set of regulatory elements that have to be finely and constantly tuned to maintain local homeostasis. These environments could be site specific, such as the gut environment, or induced by chronic exposure to microbes. Various populations of dendritic cells are central to the orchestration of this control. In this review, we discuss some new findings associating dendritic cells from defined compartments with the induction and control of regulatory T cells in the context of exposure to both commensal and pathogenic microbes. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296082 Mon, 22 Feb 2010 00:00:00 +0100 3296082 http://www.medworm.com/index.php?rid=3296081&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00873.x Summary: The eye and the brain are immunologically privileged sites, a property previously attributed to the lack of a lymphatic circulation. However, recent tracking studies confirm that these organs have good communication through classical site-specific lymph nodes, as well as direct connection through the blood circulation with the spleen. In addition, like all tissues, they contain resident myeloid cell populations that play important roles in tissue homeostasis and the response to foreign antigens. Most of the macrophage and dendritic cell (DC) populations in the eye are restricted to the supporting connective tissues, including the cornea, while the neural tissue (the retina) contains almost no DCs, occasional macrophages (perivascularly distributed), and a specialized myeloid cell ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296081 Mon, 22 Feb 2010 00:00:00 +0100 3296081 http://www.medworm.com/index.php?rid=3296080&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00874.x Summary: CD103 ([alpha]E) integrin expression distinguishes a population of dendritic cells (DCs) that can be found in many if not all lymphoid and non-lymphoid organs. CD103+ DCs display distinct functional activities. Migratory CD103+ DCs derived from skin, lung, and intestine efficiently present exogenous antigens in their corresponding draining lymph nodes to specific CD8+ T cells through a mechanism known as cross-presentation. On the T cells they prime, intestinal CD103+ DCs can drive the induction of the chemokine receptor CCR9 and [alpha]4[beta]7 integrin, both known as gut-homing receptors. CD103+ DCs also contribute to control inflammatory responses and intestinal homeostasis by fostering the conversion of naive T cells into induced Foxp3+ regulatory T cells, a mechanism that rel... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296080 Mon, 22 Feb 2010 00:00:00 +0100 3296080 http://www.medworm.com/index.php?rid=3296079&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00866.x Summary: Dendritic cells (DCs) in the intestine are heterogeneous. Phenotypically different populations of conventional DCs have been identified in the intestinal lamina propria, Peyer's patches, and in the draining mesenteric lymph nodes, to which these DCs constitutively migrate. Markers used to identify these populations include major histocompatibility complex class II, CD11c, CD8[alpha], CD11b, and CD103. Extensive studies in rats, summarized here, which involved collection of migrating DCs by thoracic duct cannulation after mesenteric lymphadenectomy, have clearly demonstrated that the subsets of migrating intestinal lymph DCs have different functional properties. The subsets might play different roles in the induction of oral tolerance and in driving systemic immune responses after ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296079 Mon, 22 Feb 2010 00:00:00 +0100 3296079 http://www.medworm.com/index.php?rid=3296078&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00872.x Summary: The healthy gut consists of the commensal flora, the epithelial layer, and the gut-associated lymphoid tissues (GALT). The GALT need to be hyporesponsive to commensal and dietary antigens while possessing the capacity to detect and attack pathogens. Accumulating evidence suggests that dendritic cells (DCs) play integral roles in managing this paradoxical situation and maintaining the complex homeostasis in the gut, which includes the induction of immunoglobulin A (IgA) synthesis. This review outlines the roles of the commensal flora, epithelial layer, and GALT in mucosal homeostasis and inflammatory conditions and highlights recent progress in our understanding of how DCs are involved in IgA synthesis in the gut. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296078 Mon, 22 Feb 2010 00:00:00 +0100 3296078 http://www.medworm.com/index.php?rid=3296077&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00878.x Summary: Dendritic cells (DCs) are key regulators of the immune system. They act as professional antigen-presenting cells and are capable of activating naive T cells and stimulating the growth and differentiation of B cells. According to their molecular expression, DCs can be divided into several subsets with different functions. We focus on DC subsets expressing langerin, a C-type lectin. Langerin expression is predominant in skin DCs, but langerin-expressing DCs also exist in mucosal tissue and can be induced by immunization and sometimes by nutrient deficiency. Topical transcutaneous immunization induces langerin+CD8[alpha][minus] DCs in mesenteric lymph nodes (MLNs), which mediate the production of antigen-specific immunoglobulin A antibody in the intestine. Yet, in one recent study, l... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296077 Mon, 22 Feb 2010 00:00:00 +0100 3296077 http://www.medworm.com/index.php?rid=3296075&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00883.x Summary: In its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from self-resolving or well manageable to severe and even fatal. LCH lesions in skin, bone, and other sites contain high numbers of cells with phenotypic features resembling LCs admixed with macrophages, T cells, eosinophils, and multinucleated giant cells. Here we review current progress in the LCH field based on two central questions: (i) are LCH cells intrinsically aberrant, and (ii) how does the lesion drive pathogenesis? We argue that LCH cells may originate from different sources, including epidermal LCs, tissue Langerin+ DCs, or mononuclear phagocyte precursors. Current and prospective... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296075 Mon, 22 Feb 2010 00:00:00 +0100 3296075 http://www.medworm.com/index.php?rid=3296073&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00884.x Summary: Immunity results from a complex interplay between the antigen-non-specific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determi... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296073 Mon, 22 Feb 2010 00:00:00 +0100 3296073 http://www.medworm.com/index.php?rid=3296072&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00868.x Summary: During evolution, vertebrates have developed an adaptive immune system able to cope with a variety of pathogens. Dendritic cells (DCs) are central to this process. DCs integrate information derived from pathogens or endogenous danger signals and convey them to T lymphocytes. Most of the present knowledge on DCs was generated in mice or by using human DCs differentiated in vitro from monocytes. In both species, several DC subsets have been identified in vivo based on differences in their phenotypes, anatomical locations or functions. In mice, protective immunity against intracellular pathogens or tumors can be induced most efficiently by targeting antigens to the CD8[alpha]+ DCs, a subset of DCs which resides in lymphoid tissues and is especially efficient at cross-presenting exoge... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296072 Mon, 22 Feb 2010 00:00:00 +0100 3296072 http://www.medworm.com/index.php?rid=3296071&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00867.x Summary: Plasmacytoid dendritic cells (pDCs) are specialized dendritic cells (DCs) that produce large amounts of type I interferon (IFN) after Toll-like receptor (TLR) activation. Human pDCs preferentially express immunoglobulin-like transcript 7 (ILT7; LILRA4), which couples with a signaling adapter to activate a prominent immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling pathway. ILT7 protein directly binds to and can be activated by bone marrow stromal cell antigen 2 (BST2; CD317) protein, the expression of which is found on cells pre-exposed to IFN or on the surface of human cancer cells. The interaction between ILT7 and BST2 functions to assure an appropriate TLR response by pDCs during viral infection and likely participates in pDC-tumor crosstalk. Two opposing... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296071 Mon, 22 Feb 2010 00:00:00 +0100 3296071 http://www.medworm.com/index.php?rid=3296070&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00881.x Summary: Plasmacytoid dendritic cells (pDCs) are bone marrow-derived cells that secrete large amounts of type I interferon (IFN) in response to viruses. Type I IFNs are pleiotropic cytokines with antiviral activity that also enhance innate and adaptive immune responses. Viruses trigger activation of pDCs and type I IFN responses mainly through the Toll-like receptor pathway. However, a variety of activating and inhibitory pDC receptors fine tune the amplitude of type I IFN responses. Chronic activation and secretion of type I IFN in the absence of infection can promote autoimmune diseases. Furthermore, while activated pDCs promote immunity and autoimmunity, resting or alternatively activated pDCs may be tolerogenic. The various roles of pDCs have been extensively studied in vitro and in vi... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296070 Mon, 22 Feb 2010 00:00:00 +0100 3296070 http://www.medworm.com/index.php?rid=3296069&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00886.x Summary: Langerhans cells (LCs) are antigen-presenting dendritic cells (DCs) that reside in epithelia. The best studied example is the LC of the epidermis. By electron microscopy, their identifying feature is the unique rod- or tennis racket-shaped Birbeck granule. The phenotypic hallmark is their expression of the C-type lectin receptor langerin/CD207. Langerin, however, is also expressed on a recently discovered population of DC in the dermis and other tissues of the body. These 'dermal langerin+ dendritic cells' are unrelated to LCs. The complex field of langerin-negative dermal DCs is not dealt with here. In this article, we briefly review the history, ontogeny, and homeostasis of LCs. More emphasis is laid on the discussion of functional properties in vivo. Novel models using genetica... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296069 Mon, 22 Feb 2010 00:00:00 +0100 3296069 http://www.medworm.com/index.php?rid=3296068&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00871.x Summary: The process of dendritic cell differentiation is governed by a tightly controlled signaling network regulated by cytokines and direct interaction between progenitor cells and bone marrow stroma. Notch signaling represents one of the major pathways activated during direct interaction between hematopoietic progenitor cells and bone marrow stroma. Wnt pathway is activated by soluble proteins produced by bone marrow stroma. Until recently, the role of Notch and Wnt signaling in the development of myeloid cells and dendritic cells in particular remained unclear. In this review, we discuss recent exciting findings that shed light on the critical role of Notch and Wnt pathways, their interaction in differentiation and function of dendritic cells, and their impact on immune responses. (So... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296068 Mon, 22 Feb 2010 00:00:00 +0100 3296068 http://www.medworm.com/index.php?rid=3296067&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00876.x Summary: Although monocytes were originally described as precursors to all the different subpopulations of macrophages found in the steady state and formed under inflammatory and infectious conditions, recent data have demonstrated conclusively that monocytes can also differentiate into dendritic cells (DCs). Monocytes are the precursors to different subsets of DCs, such as Langerhans cells and DCs found in the lamina propria of the gastrointestinal, respiratory, and urogenital tracts. In addition, monocyte-derived DCs (moDCs), newly formed during inflammatory reactions, appear to fulfill an essential role in defense mechanisms against pathogens by participating in the induction of both adaptive and innate immune responses. In this regard, moDCs have the capacity to activate antigen-specif... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296067 Mon, 22 Feb 2010 00:00:00 +0100 3296067 http://www.medworm.com/index.php?rid=3296066&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00875.x Summary: Recent years have seen a major advance in our understanding of the organization of the dendritic cell (DC) compartment. Particularly rewarding in this respect have been studies investigating DC origins, based on the identification of transcription factor and growth factor requirements, as well as direct demonstrations of precursor/progeny relationships by adoptive cell transfers. However, to fully understand the organization of the DC compartment, functional definitions of DC subsets must be provided and potential task divisions revealed that distinguish DC from other immune cells, including the closely related mononuclear phagocytes, such as macrophages. In fact, functional definitions might eventually replace the current distinction between DC and macrophages, which is in part b... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296066 Mon, 22 Feb 2010 00:00:00 +0100 3296066 http://www.medworm.com/index.php?rid=3296065&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00885.x Summary: Dendritic cells (DCs) have been extensively studied in mice lymphoid organs, but less is known about the origin and the mechanisms that regulate DC development and function in non-lymphoid tissues. Here, we discuss recent evidence establishing the contribution of the DC-restricted lineage to the non-lymphoid tissue DC pool and discuss the mechanisms that control the homeostasis of non-lymphoid tissue DCs. We also review recent results underlining the functional specialization of tissue DCs and discuss the potential implications of these findings in tissue immunity and in the development of novel vaccine strategies. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296065 Mon, 22 Feb 2010 00:00:00 +0100 3296065 http://www.medworm.com/index.php?rid=3296064&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00879.x Summary: Dendritic cells (DCs) are specialized antigen-presenting cells and essential mediators of immunity and tolerance. This group of cells is heterogeneous in terms of cell-surface markers, anatomic location, and function. Here, we review the development and function of DCs found in lymphoid and non-lymphoid tissues in the steady state. DC and monocyte lineages originate from a common progenitor, the monocyte and dendritic cell progenitor (MDP). The two cell types diverge when MDPs give rise to monocytes and committed DC progenitors (CDPs) in the bone marrow. CDPs give rise to pre-DCs, which migrate from the bone marrow to lymphoid and non-lymphoid tissues to produce the two major subpopulations of lymphoid tissue DCs and non-lymphoid tissue CD103+ DCs. Within tissues and during develo... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296064 Mon, 22 Feb 2010 00:00:00 +0100 3296064 http://www.medworm.com/index.php?rid=3296063&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00877.x Summary: Clarifying the signals that lead to dendritic cell (DC) development and identifying cellular intermediates on their way to DC differentiation are essential steps to understand the dynamic regulation of number, localization, and functionality of these cells. In the past decade, much knowledge on cytokines, transcription factors, and successive progenitors involved in steady-state and demand-adapted DC development was gained. From the stage of multipotent progenitors, DCs are generated from Flt3+ intermediates, irrespective of lymphoid or myeloid commitment, making fms-related tyrosine kinase 3 ligand one of the major regulators for DC development. Additional key cytokines involved are granulocyte[ndash]macrophage colony-stimulating factor (GM-CSF) and M-CSF, with each being essenti... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296063 Mon, 22 Feb 2010 00:00:00 +0100 3296063 http://www.medworm.com/index.php?rid=3296062&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00870.x Summary: Mouse lymphoid tissues contain a subset of dendritic cells (DCs) expressing CD8[alpha] together with a pattern of other surface molecules that distinguishes them from other DCs. These molecules include particular Toll-like receptor and C-type lectin pattern recognition receptors. A similar DC subset, although lacking CD8 expression, exists in humans. The mouse CD8+ DCs are non-migrating resident DCs derived from a precursor, distinct from monocytes, that continuously seeds the lymphoid organs from bone marrow. They differ in several key functions from their CD8[minus] DC neighbors. They efficiently cross-present exogenous cell-bound and soluble antigens on major histocompatibility complex class I. On activation, they are major producers of interleukin-12 and stimulate inflammatory... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3296062 Mon, 22 Feb 2010 00:00:00 +0100 3296062 http://www.medworm.com/index.php?rid=3120815&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00869.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120815 Fri, 25 Dec 2009 22:52:01 +0100 3120815 http://www.medworm.com/index.php?rid=3120833&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00857.x Summary: The past decade has observed an explosion of new information regarding the impact of inflammation on bone. In rheumatic diseases, several factors that act as both immune modulators and regulators of bone homeostasis have been shown to mediate an imbalance in bone resorption and bone formation resulting in joint degeneration. In rheumatoid arthritis (RA), focal bone loss is due to excess bone resorption by osteoclasts. Resorption is mediated in part by increased local expression of the cytokine receptor activator of nuclear factor-[kappa]B ligand (RANKL) compared with expression of its decoy receptor osteoprotegerin (OPG). Bone formation by osteoblasts is also impaired at erosion sites in RA, and inhibitors of the canonical Wingless (Wnt) signaling pathway, including DKK1, have bee... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120833 Wed, 23 Dec 2009 00:00:00 +0100 3120833 http://www.medworm.com/index.php?rid=3120832&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00849.x Summary: Osteoporosis and arthritis are highly prevalent diseases and a significant cause of morbidity and mortality worldwide. These diseases result from aberrant tissue remodeling leading to weak, fracture-prone bones or painful, dysfunctional joints. The nuclear factor of activated T cells (NFAT) transcription factor family controls diverse biologic processes in vertebrates. Here, we review the scientific evidence that links NFAT-regulated gene transcription to bone and joint pathology. A particular emphasis is placed on the role of NFATs in bone resorption and formation by osteoclasts and osteoblasts, respectively. In addition, emerging data that connect NFATs with cartilage biology, angiogenesis, nociception, and neurogenic inflammation are explored. The goal of this article is to hig... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120832 Wed, 23 Dec 2009 00:00:00 +0100 3120832 http://www.medworm.com/index.php?rid=3120831&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00861.x Summary: Rheumatoid arthritis is a chronic systemic inflammatory disease primarily affecting the synovium of diarthrodial joints. Despite the currently unknown etiology, overwhelming evidence indicates that both innate and adaptive immunity play a central role in disease pathogenesis. In this review, we consider recent evidence examining the mechanisms of lymphoid tissue reactivity in rheumatoid arthritis with a focus on the dynamics controlling secondary and ectopic lymphoid tissue response. We then examine the cellular and molecular mechanisms regulating the biopathology of these processes with specific emphasis on cell trafficking, contribution to autoimmunity, and joint damage-repair. We finally provide a brief overview of the most recent studies addressing the clinical relevance of sy... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120831 Wed, 23 Dec 2009 00:00:00 +0100 3120831 http://www.medworm.com/index.php?rid=3120830&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00854.x Summary: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joint synovium. The normal synovium consists of a lining layer of fibroblast-like synoviocytes (FLS) and macrophages, one to three cells deep that overlies the loose connective tissue of the synovial sublining. During the course of RA, the synovium is the site of inflammation where immune cells are massively infiltrated, and the lining layer becomes hyperplastic and transforms into a pannus tissue that destroys articular cartilage and bone. FLS play an important role in this RA pathogenesis. In this review, we explain that cadherin-11, an adhesion molecule, is selectively expressed on FLS and required for synovial lining formation. In addition, cadherin-11 on FLS contributes to synovial inflammati... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120830 Wed, 23 Dec 2009 00:00:00 +0100 3120830 http://www.medworm.com/index.php?rid=3120829&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00859.x Summary: Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into diseas... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120829 Wed, 23 Dec 2009 00:00:00 +0100 3120829 http://www.medworm.com/index.php?rid=3120828&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00860.x Summary: Gout is an arthritis characterized by elevated uric acid in the bloodstream. In this condition, crystals of uric acid are formed and accumulate in the synovial fluids. Crystal deposition leads to acute inflammation, which is associated with the spontaneous resolution of the disease. Recent studies have led to significant advances in the understanding of the basic biology of crystal-mediated inflammation. Uric acid has been identified as a danger signal that triggers a cytosolic sensor, the inflammasome. This signaling platform is required for the activation of interleukin-1, a cytokine that is critical to the initiation of acute inflammation in gout. Importantly, both molecular and pathological evidence support the notion that gout is a prototypical member of the growing family of... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120828 Wed, 23 Dec 2009 00:00:00 +0100 3120828 http://www.medworm.com/index.php?rid=3120827&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00851.x Summary: Uric acid crystals [monosodium urate (MSU)] have emerged as an important factor for both gouty arthritis and immune regulation. This simple crystalline structure appears to activate innate host defense mechanisms in multiple ways and triggers robust inflammation and immune activation. The recognition mechanisms of MSU following its phase change from soluble uric acid are diverse, involving both protein receptors and non-specific plasma membrane attachment. Upon contact with host cells, MSU induces a set of membrane events that trigger Syk and PI3K activation, phagocytosis, and cytokine production. Having entered the cell, MSU further triggers NALP3 inflammasome activation and induces the production of IL-1[beta], likely inducing a full spectrum of inflammation. This review describ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120827 Wed, 23 Dec 2009 00:00:00 +0100 3120827 http://www.medworm.com/index.php?rid=3120826&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00865.x Summary: Almost four decades of research into the role of human leukocyte antigen-B27 (HLA-B27) in susceptibility to spondyloarthritis has yet to yield a convincing answer. New results from an HLA-B27 transgenic rat model now demonstrate quite convincingly that CD8+ T cells are not required for the inflammatory phenotype. Discoveries that the HLA-B27 heavy chain has a tendency to misfold during the assembly of class I complexes in the endoplasmic reticulum (ER) and to form aberrant disulfide-linked dimers after transport to the cell surface have forced the generation of new ideas about its role in disease pathogenesis. In transgenic rats, HLA-B27 misfolding generates ER stress and leads to activation of the unfolded protein response, which dramatically enhances the production of interleuki... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120826 Wed, 23 Dec 2009 00:00:00 +0100 3120826 http://www.medworm.com/index.php?rid=3120825&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00852.x Summary: Ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the pathogenesis of which is poorly understood. The mechanism by which the main gene for the disease, HLA-B27, leads to AS is unknown. Genetic and genomic studies have demonstrated involvement of the interleukin-23 (IL-23) signaling pathway in AS, a finding which has stimulated much new research into the disease and has led to therapeutic trials. Several other genes and genetic regions, including further major histocompatibility complex (MHC) and non-MHC loci, have been shown to be involved in the disease, but it is not clear yet how they actually induce the condition. These findings have shown that there is a strong genetic overlap between AS and Crohn's disease in particular, although there are also major dif... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120825 Wed, 23 Dec 2009 00:00:00 +0100 3120825 http://www.medworm.com/index.php?rid=3120824&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00855.x Summary: B lymphocytes contribute to immunity through production of antibodies, antigen presentation to T cells, and secretion of cytokines. B cells are generally considered in autoimmune diseases as drivers of pathogenesis. This view is certainly justified, given the successful utilization of the B cell-depleting reagent rituximab in patients with rheumatoid arthritis or other autoimmune pathologies. In a number of cases, however, the depletion of B cells led to an exacerbation of symptoms in patients with autoimmune disorders. In a similar manner, mice lacking B cells can develop an aggravated course of disease in several autoimmune models. These paradoxical observations are now explained by the concept that activated B cells can suppress immune responses through the production of cytoki... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120824 Wed, 23 Dec 2009 00:00:00 +0100 3120824 http://www.medworm.com/index.php?rid=3120823&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00863.x Summary: The U1 small nuclear ribonucleoprotein particle (snRNP) is a target of autoreactive B cells and T cells in several rheumatic diseases including systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). We propose that inherent structural properties of this autoantigen complex, including common RNA-binding motifs, B and T-cell epitopes, and a unique stimulatory RNA molecule, underlie its susceptibility as a target of the autoimmune response. Immune mechanisms that may contribute to overall U1-snRNP immunogenicity include epitope spreading through B and T-cell interactions, apoptosis-induced modifications, and Toll-like receptor (TLR) activation through stimulation by U1-snRNA. We conclude that understanding the interactions between U1-snRNP and the immune syste... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120823 Wed, 23 Dec 2009 00:00:00 +0100 3120823 http://www.medworm.com/index.php?rid=3120822&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00856.x Summary: Inflammatory arthritis presents in a variety of diseases, from rheumatoid arthritis to hepatitis. Antibodies to autoantigens or to microbial constituents are commonly associated with these conditions. In some cases, the antibodies have diagnostic and prognostic relevance. It cannot as yet be determined definitively that any of them mediate joint damage, although the evidence from animal models indicates that this mechanism is likely. The purpose of this article is to give an overview of the spectrum of antibodies found in a variety of inflammatory arthritides. The relevant animal models are also discussed. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120822 Wed, 23 Dec 2009 00:00:00 +0100 3120822 http://www.medworm.com/index.php?rid=3120821&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00848.x Summary: CD4+CD25+ regulatory T (Treg) cells can play a critical role in the prevention of autoimmunity, as evidenced by the cataclysmic autoimmune disease that develops in mice and humans lacking the key transcription factor forkhead box protein 3 (Foxp3). At present, however, how and whether Treg cells participate in the development of rheumatoid arthritis (RA), which has both systemic manifestations and a joint-targeted pathology that characterizes the disease, remains unclear. In this review, we describe work that has been carried out aimed at determining the role of Treg cells in disease development in RA patients and in mouse models of inflammatory arthritis. We also describe studies in a new model of spontaneous autoimmune arthritis (TS1 × HACII mice), in which disease is caused by... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120821 Wed, 23 Dec 2009 00:00:00 +0100 3120821 http://www.medworm.com/index.php?rid=3120820&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00864.x Summary: Accumulating evidence from murine and human studies supports a key role for interleukin-17 (IL-17) and IL-21 in the pathogenesis of inflammatory arthritis. The pathways and molecular mechanisms that underlie the production of IL-17 and IL-21 are being rapidly elucidated. This review focuses on interferon regulatory factor 4 (IRF4), a member of the IRF family of transcription factors, which has emerged as a crucial controller of both IL-17 and IL-21 production. We first outline the complex role of IRF4 in the function of CD4+ T cells and then discuss recent studies from our laboratory that have revealed a surprising role for components of Rho GTPase-mediated pathways in controlling the activity of IRF4. A better understanding of these novel pathways will hopefully provide new insig... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120820 Wed, 23 Dec 2009 00:00:00 +0100 3120820 http://www.medworm.com/index.php?rid=3120819&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00858.x Summary: Predisposition to develop rheumatoid arthritis (RA) has been associated with certain human leukocyte antigen (HLA) class II molecules, although the mechanism is still unknown. Various experimental animal models of inflammatory arthritis have been studied to address the role of major histocompatibility complex (MHC) genes in pathogenesis. We have generated transgenic mice expressing HLA class II molecules (DR and DQ) lacking complete endogenous class II molecules to study the interactions involved between class II molecules (DQ and DR) and to define the immunologic mechanisms in inflammatory arthritis. The HLA transgene can positively select CD4+ T cells expressing various V[beta] T-cell receptors, and a peripheral tolerance is maintained to transgenic HLA molecules. The expression... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120819 Wed, 23 Dec 2009 00:00:00 +0100 3120819 http://www.medworm.com/index.php?rid=3120818&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00862.x Summary: During the past several years, substantial progress has been made in the identification of genetic variants that predispose to rheumatoid arthritis (RA) and other autoimmune disorders. Progress in this area has been facilitated by the availability of new technology that allows for a much more comprehensive screen of the genome than was possible before, in conjunction with large samples of RA patients with well-characterized disease. Recent RA genetic studies have identified genes with important functions related to intracellular signaling mechanisms, transcription factors, cytokines, membrane receptors, costimulatory molecules, and enzymes. In particular, recent discoveries highlight the importance of the CD40/NF-[kappa]B signaling pathway in RA, based on genetic association with ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120818 Wed, 23 Dec 2009 00:00:00 +0100 3120818 http://www.medworm.com/index.php?rid=3120817&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00850.x Summary: Rheumatoid arthritis (RA) is now clearly a true autoimmune disease with accumulating evidence of pathogenic disease-specific autoimmunity to citrullinated proteins. Citrullination, also termed deimination, is a modification of arginine side chains catalyzed by peptidylarginine deiminase (PAD) enzymes. This post-translational modification has the potential to alter the structure, antigenicity, and function of proteins. In RA, antibodies to cyclic citrullinated peptides are now well established for clinical diagnosis, though we argue that the identification of specific citrullinated antigens, as whole proteins, is necessary for exploring pathogenic mechanisms. Four citrullinated antigens, fibrinogen, vimentin, collagen type II, and [alpha]-enolase, are now well established, with oth... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120817 Wed, 23 Dec 2009 00:00:00 +0100 3120817 http://www.medworm.com/index.php?rid=3120816&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.0105-2896.2009.00853.x Summary: The discovery of antibodies specific for citrullinated protein epitopes [anti-citrullinated protein antibodies (ACPAs)] is a hallmark for the diagnosis and prognosis of rheumatoid arthritis (RA) and will also be a useful tool for understanding the fundamental pathologic processes. There are several essential questions pertaining to ACPA that remain to be explored, such as understanding the early specificity of the underlying T-cell recognition, whether the production of ACPA is a primary or secondary process, and in the event of such antibodies being arthritogenic, whether they could possibly regulate the disease development. To answer these questions, animal models are needed, but unfortunately ACPA is not a prominent feature of any of the classical animal models of RA. However, ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=3120816 Wed, 23 Dec 2009 00:00:00 +0100 3120816 http://www.medworm.com/index.php?rid=2925018&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00847.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925018 Sun, 25 Oct 2009 20:18:02 +0100 2925018 http://www.medworm.com/index.php?rid=2925041&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00830.x Summary: Proteases control many vital aspects of humoral and cellular immune responses, including the maturation of cytokines and the killing of target cells. Recently, it has become evident that triggering of the T-cell receptor controls T-cell proliferation through proteases such as mucosa-associated lymphoid tissue 1 (MALT1) and Caspase-8 that act both as adapters and enzymes. Here, we discuss the role of these and other proteases that are relevant to the control of the T-cell response and represent interesting targets of therapeutic immunomodulation. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925041 Fri, 23 Oct 2009 00:00:00 +0100 2925041 http://www.medworm.com/index.php?rid=2925040&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00839.x Summary: SWAP-70-like adapter of T cells (SLAT) is a recently identified guanine nucleotide exchange factor (GEF) for Cdc42 and Rac1, which is highly expressed in both thymocytes and peripheral T cells. Here, we present and discuss findings resulting from biochemical and genetic analyses aimed at unveiling the role of SLAT in CD4+ T-cell development, activation, and T-helper (Th) cell differentiation. Slat[minus]/[minus] mice display a developmental defect at one of the earliest stages of thymocyte differentiation, the double negative 1 (DN1) stage, leading to decreased peripheral T-cell numbers. Slat[minus]/[minus] peripheral CD4+ T cells demonstrate impaired T-cell receptor/CD28-induced proliferation and IL-2 production. Moreover, SLAT positively regulates the development of Th1 and Th2 ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925040 Fri, 23 Oct 2009 00:00:00 +0100 2925040 http://www.medworm.com/index.php?rid=2925039&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00836.x Summary: The transcription factor nuclear factor-[kappa]B (NF-[kappa]B) contributes to many events in the immune system. Characterization of NF-[kappa]B has facilitated our understanding of immune cell differentiation, survival, proliferation, and effector functions. Intense research continues to elucidate the role of NF-[kappa]B, which is shared in several receptor signaling pathways, such as Toll-like receptors, the tumor necrosis factor receptor, and antigen receptors. The specificity of cellular responses emanating from stimulation of these receptors is determined by post-translational modification, or 'fine tuning', which regulates spatiotemporal dynamics of downstream signaling. Understanding the fine tuning mechanisms of NF-[kappa]B activation is crucial for insights into biological... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925039 Fri, 23 Oct 2009 00:00:00 +0100 2925039 http://www.medworm.com/index.php?rid=2925038&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00837.x Summary: Development, survival, and activation of B lymphocytes are controlled by signals emanating from the B-cell antigen receptor (BCR). The BCR has an autonomous signaling function also known as tonic signaling that allows for long-term survival of B cells in the immune system. Upon binding of antigen to the BCR, the tonic signal is amplified and diversified, leading to alteration in gene expression and B-cell activation. The spleen tyrosine kinase (Syk) intimately cooperates with the signaling subunits of the BCR and plays a central role in the amplification and diversification of BCR signals. In this review, we discuss the molecular mechanisms by which Syk activity is inhibited and activated at the BCR. Importantly, Syk acts not only as a kinase that phosphorylates downstream substra... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925038 Fri, 23 Oct 2009 00:00:00 +0100 2925038 http://www.medworm.com/index.php?rid=2925037&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00844.x Summary: The mammalian Dok protein family has seven members (Dok-1[ndash]Dok-7). The Dok proteins share structural similarities characterized by the NH2-terminal pleckstrin homology and phosphotyrosine-binding domains followed by SH2 target motifs in the COOH-terminal moiety, indicating an adapter function. Indeed, Dok-1 was originally identified as a 62 kDa protein that binds with p120 rasGAP, a potent inhibitor of Ras, upon tyrosine phosphorylation by a variety of protein tyrosine kinases. Among the Dok family, only Dok-1, Dok-2, and Dok-3 are preferentially expressed in hematopoietic/immune cells. Dok-1 and its closest relative Dok-2 act as negative regulators of the Ras[ndash]Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is believed that recruitment o... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925037 Fri, 23 Oct 2009 00:00:00 +0100 2925037 http://www.medworm.com/index.php?rid=2925036&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00838.x Summary: Signaling via phosphoinositide 3-kinases (PI3Ks) has emerged as a central component of lymphocyte activation via immunoreceptors, costimulatory receptors, cytokine receptors, and chemokine receptors. The discovery of phosphoinositide-binding pleckstrin homology (PH) domains has substantially increased understanding of how PI3Ks activate cellular responses. Accumulating evidence indicates that PH-domain containing adapter molecules provide important links between PI3K and lymphocyte function. Here, we review data on PI3K-regulated adapter proteins of the Grb-associated binder (GAB), Src kinase-associated phosphoprotein (SKAP), and B-lymphocyte adapter molecule of 32 kDa (Bam32)/ dual-adapter for phosphotyrosine and 3-phosphoinositides (DAPP)/TAPP families, with a focus on the latte... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925036 Fri, 23 Oct 2009 00:00:00 +0100 2925036 http://www.medworm.com/index.php?rid=2925035&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00829.x Summary: Adapter proteins play key roles in intracellular signal transduction through complex formation with catalytically active signaling molecules. In T lymphocytes, the role of several different types of adapter proteins in T-cell antigen receptor signal transduction is well established. An exception to this is the family of T-cell-specific adapter (TSAd) proteins comprising of TSAd, adapter protein of unknown function (ALX), SH2D4A, and SH2D4B. Only recently has the function of these adapters in T-cell signal transduction been explored. Here, we discuss advances in our understanding of the role of this family of adapter proteins in T cells. Their function as regulators of signal transduction in other cell types is also discussed. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925035 Fri, 23 Oct 2009 00:00:00 +0100 2925035 http://www.medworm.com/index.php?rid=2925034&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00824.x Summary: The signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) family of adapters includes SAP, Ewing's sarcoma-associated transcript-2 (EAT-2), and EAT-2-related transducer (ERT). These Src homology-2 (SH2) domain-only molecules play critical roles in immune regulation. The prototype of the SAP family, SAP, is mutated in X-linked lymphoproliferative disease in humans. Moreover, genetically engineered mice lacking one or more SAP family members have defects in multiple immune cell types including T cells, natural killer (NK) cells, NKT cells, and B cells. Accumulating data show that SAP family adapters regulate immunity by influencing the functions of SLAM family receptors, through two distinct but cooperative mechanisms. First, SAP family adapters couple SLAM famil... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925034 Fri, 23 Oct 2009 00:00:00 +0100 2925034 http://www.medworm.com/index.php?rid=2925033&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00827.x Summary: Src-like adapter proteins (SLAP and SLAP-2) constitute a family of proteins that are expressed in a variety of cell types but are studied most extensively in lymphocytes. They have been shown to associate with proximal components of the T-cell receptor (TCR) and B-cell receptor (BCR) signaling complexes. An interaction of SLAP with c-Cbl leads to the ubiquitination and degradation of phosphorylated components of the TCR- and BCR-signaling complexes. The absence of this process in immature SLAP-deficient T and B cells leads to increased immunoreceptor levels due to decreased intracellular retention and degradation. We propose a model in which SLAP-dependent regulation of immunoreceptor levels allows for finer control of immunoreceptor signaling. Thus, SLAP functions to dampen immun... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925033 Fri, 23 Oct 2009 00:00:00 +0100 2925033 http://www.medworm.com/index.php?rid=2925032&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00834.x Summary: Mast cells are pivotal in innate immunity and play an important role in amplifying adaptive immunity. Nonetheless, they have long been known to be central to the initiation of allergic disorders. This results from the dysregulation of the immune response whereby normally innocuous substances are recognized as non-self, resulting in the production of IgE antibodies to these 'allergens'. Preformed and newly synthesized inflammatory (allergic) mediators are released from the mast cell following allergen-mediated aggregation of allergen-specific IgE bound to the high-affinity receptors for IgE (Fc[epsilon]RI). Thus, the process by which the mast cell is able to interpret the engagement of Fc[epsilon]RI into the molecular events necessary for release of their allergic mediators is of c... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925032 Fri, 23 Oct 2009 00:00:00 +0100 2925032 http://www.medworm.com/index.php?rid=2925031&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00846.x Summary: Cytoskeletal structure and dynamic rearrangement are integrally involved in coupling external stimuli to the orchestrated network of molecular interactions and cellular responses required for T-cell effector function. Members of the Wiskott[ndash][ndash]Aldrich syndrome protein (WASp) family are now widely recognized as cytoskeletal scaffolding adapters that coordinate the transmission of stimulatory signals to downstream induction of actin remodeling and cytoskeletal-dependent T-cell responses. In this review, we discuss the structural and functional properties of the WASp family members, with an emphasis on the roles of these proteins in the molecular pathways underpinning T-cell activation. The contributions of WASp family proteins and the cytoskeletal reorganization they evoke... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925031 Fri, 23 Oct 2009 00:00:00 +0100 2925031 http://www.medworm.com/index.php?rid=2925030&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00831.x Summary: The Cas family of proteins consists of at least four members implicated in the regulation of diverse cellular processes such as cell proliferation, adhesion, motility, and cancer cell metastasis. Cas family members have conserved C-termini that mediate constitutive heterotypic interactions with members of a different group of proteins, the NSP family. Both the Cas and NSP proteins have conserved domains that mediate protein[ndash]protein interactions with other cytoplasmic intermediates. Signaling modules assembled by these proteins in turn regulate signal transduction downstream of a variety of receptors including integrin, chemokine, and antigen receptors. T lymphocytes express the NSP protein NSP3/Chat-H and the Cas protein Hef1/CasL, which are found in a constitutive complex i... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925030 Fri, 23 Oct 2009 00:00:00 +0100 2925030 http://www.medworm.com/index.php?rid=2925029&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00842.x Summary: Lymphocyte development, activation, and tolerance depend on antigen receptor signaling transduced via multiple intracellular signalosomes. These signalosomes are assembled by different adapters. Given that signaling molecules can be either positive or negative regulators for a biochemical target, the complex of a target with different regulator may dictate the final signaling outcome. Grb2 is a simple adapter known to be involved in a variety of growth factor receptor signaling. However, its role in antigen receptor signaling as well as lymphocyte development and function has emerged only recently. Despite its simple molecular structure, recent experiments show that Grb2 may play a complex role in T and B-cell antigen receptor signaling. In this article, we review recent findings ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925029 Fri, 23 Oct 2009 00:00:00 +0100 2925029 http://www.medworm.com/index.php?rid=2925028&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00845.x Summary: The growth factor receptor-bound protein 2 (Grb2) is a ubiquitously expressed and evolutionary conserved adapter protein possessing a plethora of described interaction partners for the regulation of signal transduction. In B lymphocytes, the Grb2-mediated scaffolding function controls the assembly and subcellular targeting of activating as well as inhibitory signalosomes in response to ligation of the antigen receptor. Also, integration of simultaneous signals from B-cell coreceptors that amplify or attenuate antigen receptor signal output relies on Grb2. Hence, Grb2 is an essential signal integrator. The key question remains, however, of how pathway specificity can be maintained during signal homeostasis critically required for the balance between immune cell activation and toler... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925028 Fri, 23 Oct 2009 00:00:00 +0100 2925028 http://www.medworm.com/index.php?rid=2925027&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00826.x Summary: The Shc adapter family includes four members that are expressed as multiple isoforms and participate in signaling by a variety of cell-surface receptors. The biological relevance of Shc proteins as well as their variegated function, which relies on their highly conserved modular structure, is underscored by the distinct and dramatic phenotypic alterations resulting from deletion of individual Shc isoforms both in the mouse and in two model organisms, Drosophila melanogaster and Caenorhabditis elegans. The p52 isoform of ShcA couples antigen and cytokine receptors to Ras activation in both lymphoid and myeloid cells. However, the recognition of the spectrum of activities of p52ShcA in the immune system has been steadily expanding in recent years to other fundamental processes both ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925027 Fri, 23 Oct 2009 00:00:00 +0100 2925027 http://www.medworm.com/index.php?rid=2925026&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00825.x Summary: Activation of mast cells through their high-affinity immunoglobulin E receptor (Fc[epsilon]RI) plays an important role in allergic disorders. Other mast cell-activating stimuli, such as Toll-like receptor (TLR) ligands, synergize with Fc[epsilon]RI to enhance allergic inflammation. Thus, there is much interest in understanding how signaling occurs downstream of these receptors. One key event for Fc[epsilon]RI-mediated mast cell activation is the inducible formation of multimolecular proximal signaling complexes. These complexes are nucleated by adapter proteins, scaffolds that localize various signaling molecules through their multiple molecule-binding domains. Here we review recent findings in proximal signaling cascades with an emphasis on how adapter molecules cooperate with ea... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925026 Fri, 23 Oct 2009 00:00:00 +0100 2925026 http://www.medworm.com/index.php?rid=2925025&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00840.x Summary: Although the critical role of T-cell receptor (TCR) microclusters in T-cell activation is now widely accepted, the mechanisms of regulation of these TCR-rich structures, which also contain enzymes, adapters, and effectors, remain poorly defined. Soon after microcluster formation, several signaling proteins rapidly dissociate from the TCR. Recent studies from our laboratory demonstrated that the movement of the adapters linker for activation of T cells (LAT) and Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) away from initial microcluster formation sites represents endocytic events. Ubiquitylation, Cbl proteins, and multiple endocytic pathways are involved in the internalization events that disassemble signaling microclusters. Several recent studies have indi... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925025 Fri, 23 Oct 2009 00:00:00 +0100 2925025 http://www.medworm.com/index.php?rid=2925024&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00828.x Summary: Transmembrane adapter proteins (TRAPs) are critical components of signaling pathways in lymphocytes, linking antigen receptor engagement to downstream cellular processes. While these proteins lack intrinsic enzymatic activity, their phosphorylation following receptor ligation allows them to function as scaffolds for the assembly of multi-molecular signaling complexes. Many TRAPs have recently been discovered, and numerous studies demonstrate their roles in the positive and negative regulation of lymphocyte maturation, activation, and differentiation. One such example is the linker for activation of T cells (LAT) family of adapter proteins. While LAT has been shown to play an indispensable role in T-cell and mast cell function, the other family members, linker for activation of B c... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925024 Fri, 23 Oct 2009 00:00:00 +0100 2925024 http://www.medworm.com/index.php?rid=2925023&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00832.x Summary: Immune homeostasis is regulated by a finely tuned network of positive[ndash]negative regulatory mechanisms that guarantees proper surveillance avoiding hyperactivity that would lead to autoimmunity and inflammatory diseases. Immune responses involve the activation of immunoreceptors that contain tyrosine-based activation motifs (ITAMs). One arm of control involves immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors, which upon co-aggregation initiate an inhibitory signal through recruitment of signal-aborting phosphatases. Recently, a new immunoregulatory function has been ascribed to ITAMs, which represent in fact dual function modules that, under specific configurations termed inhibitory ITAM (ITAMi), can propagate inhibitory signals. One paradigm is the immu... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925023 Fri, 23 Oct 2009 00:00:00 +0100 2925023 http://www.medworm.com/index.php?rid=2925022&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00841.x Summary: The adapter proteins DAP12 and FcR[gamma] associate with a wide spectrum of receptors in a variety of innate immune cells to mediate intracellular signaling pathways when their cognate receptor is engaged. These adapter proteins are coupled to their receptors through charged residues within the transmembrane regions of the adapter and receptor. DAP12 and FcR[gamma] contain specific protein domains (referred to as immunoreceptor tyrosine-based activation motifs) that serve as the substrates and docking sites for kinases, allowing amplification of intracellular signaling reactions. Recent research has broadened the repertoire of receptors that utilize these adapters for signaling to include not only novel immunoglobulin superfamily members but also cytokine receptors, integrins, and... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925022 Fri, 23 Oct 2009 00:00:00 +0100 2925022 http://www.medworm.com/index.php?rid=2925021&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00833.x Summary: In B cells, antigen drives the formation of B-cell receptor (BCR) clusters that initiate the formation of signaling complexes associated with the cytoplasmic domains of the BCRs. These signaling active complexes contain a number of protein and lipid kinases and phosphatases and adapter and scaffolding proteins that together function to trigger downstream signaling cascades leading to the activation of a variety of genes associated with B-cell activation. Although we are learning a considerable amount about the molecular details of the assembly of immune receptor signaling complexes, as reviewed in this volume, a fundamental question remains, namely how does antigen binding outside the cell initiate the assembly of signaling complexes inside the cell. For B cells, we do not yet und... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925021 Fri, 23 Oct 2009 00:00:00 +0100 2925021 http://www.medworm.com/index.php?rid=2925020&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00835.x Summary: Assembly, expression, and signal transduction by the pre-T-cell receptor (pre-TCR) and TCR complexes are critical for normal thymocyte development. How environmental cues sensed by these two receptor complexes are translated into biological responses that result in the generation of functionally mature T cells is increasingly better understood. Invariant CD3[gamma], [delta], [epsilon], and [zeta] polypeptides are central to the function of these two receptor complexes. CD3 chains ensure correct intracellular assembly, surface expression, and signal transduction via the receptors in ligand-independent and -dependent manners. In the present review, the roles of the CD3 chains, particularly CD3[gamma], [delta], and [epsilon], in thymocyte differentiation in mice and humans are review... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925020 Fri, 23 Oct 2009 00:00:00 +0100 2925020 http://www.medworm.com/index.php?rid=2925019&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00843.x Summary: The series of events leading to T-cell activation following antigen recognition has been extensively investigated. Although the exact mechanisms of ligand binding and transmission of this extracellular interaction into a productive intracellular signaling sequence remains incomplete, it has been known for many years that the immunoreceptor tyrosine activation motifs (ITAMs) of the T-cell receptor (TCR):CD3 complex are required for initiation of this signaling cascade because of the recruitment and activation of multiple protein tyrosine kinases, signaling intermediates, and adapter molecules. It however remains unclear why the TCR:CD3 complex requires 10 ITAMs, while many other ITAM-containing immune receptors, such as Fc receptors (FcRs) and the B cell receptor (BCR), contain far... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2925019 Fri, 23 Oct 2009 00:00:00 +0100 2925019 http://www.medworm.com/index.php?rid=2782861&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00806.x Summary: Ca2+-driven responses in dendritic cells (DCs) are less well characterized than in lymphocytes. When DCs undergo a sequence of activation/maturation events, typically beginning with exposure to pathogens in the periphery, Ca2+ entry into the cytosol from stores in the endoplasmic reticulum or from outside the cell can occur at various steps and participate in intracellular signaling. However, not all cellular processes identified in these cells are Ca2+ dependent. While immigration of precursor DCs into the peripheral tissues as well as emigration to secondary lymphoid sites following microbial challenge depend on processes that involve Ca2+, other processes such as DC maturation in response to Toll-like receptor agonist stimulation appear not to. Certain microbial stimuli and hos... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782861 Wed, 09 Sep 2009 23:00:00 +0100 2782861 http://www.medworm.com/index.php?rid=2782860&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00822.x Summary: Dynamic changes in cytoplasmic calcium concentration dictate the immunological fate and functions of lymphocytes. During the past few years, important details have been revealed about the mechanism of store-operated calcium entry in lymphocytes, including the molecular identity of calcium release-activated calcium (CRAC) channels and the endoplasmic reticulum (ER) calcium sensor (STIM1) responsible for CRAC channel activation following calcium depletion of stores. However, details of the potential fine regulation of CRAC channel activation that may be imposed on lymphocytes following physiologic stimulation within an inflammatory environment have not been fully addressed. In this review, we discuss several underexplored aspects of store-operated (CRAC-mediated) and store-independe... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782860 Wed, 09 Sep 2009 23:00:00 +0100 2782860 http://www.medworm.com/index.php?rid=2782859&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00805.x Summary: T lymphocytes require Ca2+ entry though the plasma membrane for their activation and function. Recently, several routes for Ca2+ entry through the T-cell plasma membrane after activation have been described. These include calcium release-activated channels (CRAC), transient receptor potential (TRP) channels, and inositol-1,4,5-trisphosphate receptors (IP3Rs). Herein we review the emergence of a fourth new route for Ca2+ entry, composed of Cav channels (also known as L-type voltage-gated calcium channels) and the scaffold protein AHNAK1 (AHNAK/desmoyokin). Both helper (CD4+) and killer (CD8+) T cells express high levels of Cav1 [alpha]1 subunits ([alpha]1S, [alpha]1C, [alpha]1D, and [alpha]1F) and AHNAK1 after their differentiation and require these molecules for Ca2+ entry during ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782859 Wed, 09 Sep 2009 23:00:00 +0100 2782859 http://www.medworm.com/index.php?rid=2782858&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00821.x Summary: Osteoclasts are unique, multinucleated giant cells that decalcify and degrade the bone matrix. They originate from hematopoietic cells and their differentiation is dependent on a tumor necrosis factor (TNF) family cytokine, receptor activator of nuclear factor-[kappa]B (NF-[kappa]B) ligand (RANKL), as well as macrophage-colony stimulating factor (M-CSF). Recent studies have unveiled the precise molecular mechanism underlying osteoclastogenesis. In particular, the discovery of nuclear factor of activated T cells c1 (NFATc1), the master regulator of osteoclastogenesis, has proven to be a breakthrough in this field. NFATc1 is activated by Ca2+ signaling induced by the activation of the immunoglobulin-like receptor signaling associated with immunoreceptor tyrosine-based activation mot... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782858 Wed, 09 Sep 2009 23:00:00 +0100 2782858 http://www.medworm.com/index.php?rid=2782857&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00817.x Summary: Cells that escape negative selection in the thymus must be inactivated or eliminated in the periphery through a series of mechanisms that include the induction of anergy, dominant suppression by regulatory T cells, and peripheral deletion of self-reactive T cells. Calcium signaling plays a central role in the induction of anergy in T cells, which become functionally inactivated and incapable of proliferating and expressing cytokines following antigen re-encounter. Suboptimal stimulation of T cells results in the activation of a calcium/calcineurin/nuclear factor of activated T cells-dependent cell-intrinsic program of self-inactivation. The proteins encoded by those genes are required to impose a state of functional unresponsiveness through different mechanisms that include downre... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782857 Wed, 09 Sep 2009 23:00:00 +0100 2782857 http://www.medworm.com/index.php?rid=2782856&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00819.x Summary: Ca2+ signals are essential for diverse cellular functions including differentiation, effector function, and gene transcription in the immune system. In lymphocytes, sustained Ca2+ entry is necessary for complete and long-lasting activation of calcineurin/nuclear factor of activated T cells (NFAT) pathways. Engagement of immunoreceptors, such as the T-cell antigen receptor, induces store-operated Ca2+ entry (SOCE) through plasma membrane Ca2+ channels. In lymphocytes, mast cells, and other immune cell types, SOCE through highly Ca2+-selective Ca2+ release-activated Ca2+ (CRAC) channels constitute the major pathway of intracellular Ca2+ increase. A recent breakthrough in our understanding of CRAC channel function is the identification of STIM and ORAI, two essential regulators of CR... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782856 Wed, 09 Sep 2009 23:00:00 +0100 2782856 http://www.medworm.com/index.php?rid=2782855&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00818.x Summary: Store-operated Ca2+ entry (SOCE) is a mechanism used by many cells types including lymphocytes and other immune cells to increase intracellular Ca2+ concentrations to initiate signal transduction. Activation of immunoreceptors such as the T-cell receptor, B-cell receptor, or Fc receptors results in the release of Ca2+ ions from endoplasmic reticulum (ER) Ca2+ stores and subsequent activation of plasma membrane Ca2+ channels such as the well-characterized Ca2+ release-activated Ca2+ (CRAC) channel. Two genes have been identified that are essential for SOCE: ORAI1 as the pore-forming subunit of the CRAC channel in the plasma membrane and stromal interaction molecule-1 (STIM1) sensing the ER Ca2+ concentration and activating ORAI1-CRAC channels. Intense efforts in the past several ye... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782855 Wed, 09 Sep 2009 23:00:00 +0100 2782855 http://www.medworm.com/index.php?rid=2782854&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00813.x Summary: Calcium signals in immune cells regulate a variety of physiological responses such as cell activation, differentiation, gene transcription, and effector functions. Surface receptor stimulation induces an increase in the concentration of cytosolic calcium ions (Ca2+), which are derived mainly from two sources, intracellular endoplasmic reticulum (ER) Ca2+ stores and the extracellular space. The major cascade for Ca2+ entry in immune cells is through store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) channels. Activation of SOCE is triggered by depletion of intracellular ER Ca2+ stores, but the molecular mechanism was a long-standing issue. With the recent molecular identification of the ER Ca2+ sensor [stromal interacting molecule-1 (STIM1)] and a pore-forming ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782854 Wed, 09 Sep 2009 23:00:00 +0100 2782854 http://www.medworm.com/index.php?rid=2782853&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00809.x Summary: Cytotoxic T lymphocytes (CTLs) kill targets by releasing cytotoxic agents from lytic granules. Killing is a multi-step process. The CTL adheres to a target, allowing its T-cell receptors to recognize antigen. This triggers a signal transduction cascade that leads to the polarization of the microtubule cytoskeleton and granules towards the target, followed by exocytosis that occurs specifically at the site of contact. As with cytokine production by helper T cells (Th cells), target cell killing is absolutely dependent on Ca2+ influx, which is involved in regulating both reorientation and release. Current evidence suggests that Ca2+ influx in CTLs, as in Th cells, occurs via depletion-activated channels. The molecules that couple increases in Ca2+ to reorientation are unknown. The C... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782853 Wed, 09 Sep 2009 23:00:00 +0100 2782853 http://www.medworm.com/index.php?rid=2782852&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00812.x Summary: In the last few years, great progress has been made in understanding how stromal interacting molecule 1 (STIM1), a protein containing a calcium sensor that is located in the endoplasmic reticulum, and Orai1, a protein that forms a calcium channel in the plasma membrane, interact and give rise to store-operated calcium entry. Pharmacological depletion of calcium stores leads to the formation of clusters containing STIM and Orai that appear to be sites for calcium influx. Similar puncta are also produced in response to physiological stimuli in immune cells. In T cells engaged with antigen-presenting cells, clusters containing STIM and Orai accumulate at the immunological synapse. We recently discovered that in activated T cells, STIM1 and Orai1 also accumulate in cap-like structures... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782852 Wed, 09 Sep 2009 23:00:00 +0100 2782852 http://www.medworm.com/index.php?rid=2782851&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00811.x Summary: Cell polarization is a key feature of T-cell function. The immunological synapse (IS) between T cells and antigen-presenting cells is a beautiful example of how polarization of cells is used to guide cell function. Receptors, signal transducers, the cytoskeleton, and organelles are enriched at or depleted from the IS after its formation, and in many cases these re-localizations have already been linked with certain T-cell functions. One key step for T-cell activation is a rise in the cytoplasmic calcium concentration. Whereas it is undisputed that the IS initiates and controls calcium signals in T cells, very little is known about the role of T-cell polarization for calcium signals and calcium-dependent signal transduction. We briefly summarize the basic commonly agreed principles... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782851 Wed, 09 Sep 2009 23:00:00 +0100 2782851 http://www.medworm.com/index.php?rid=2782850&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00814.x Summary: The endoplasmic reticulum (ER) lumen stores a crucial source of calcium (Ca2+) maintained orders of magnitude higher than the cytosol for the activation of a plethora of cellular responses transmitted in health and disease by a mutually efficient and communicative exchange of Ca2+ between compartments. A coordination of the Ca2+ signal is evident in the development of Ca2+ release-activated Ca2+ (CRAC) entry, vital to lymphocyte activation and replenishing of the ER Ca2+ stores, where modest decreases in ER luminal Ca2+ induce sustained increases in cytosolic Ca2+ sourced from steadfast extracellular Ca2+ supplies. While protein sensors that transduce Ca2+ signals in the cytosol such as calmodulin are succinctly understood, comparative data on the ER luminal Ca2+ sensors is only r... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782850 Wed, 09 Sep 2009 23:00:00 +0100 2782850 http://www.medworm.com/index.php?rid=2782849&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00815.x Summary: Calcium (Ca2+) entry into non-excitable cells is mainly carried by store-operated channels, which serve essential functions ranging from regulation of transcription to cell growth. The best-characterized store-operated current, initially discovered in T lymphocytes and mast cells, is the Ca2+ release-activated Ca2+ (CRAC) current. The search for the molecular components of the CRAC channel has recently identified stromal interaction molecule 1 (STIM1) as the Ca2+ sensor in the endoplasmic reticulum (ER) and Orai1 as the CRAC channel pore. ER store depletion results in formation of STIM1 puncta that trigger Ca2+ influx via Orai1 channels. This review covers the role of domains within STIM1 and Orai and enlightens their function in the STIM1/Orai coupling process. Moreover, a molecu... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782849 Wed, 09 Sep 2009 23:00:00 +0100 2782849 http://www.medworm.com/index.php?rid=2782848&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00820.x Summary: The Ca2+release-activated Ca2+ (CRAC) channel is a highly Ca2+-selective store-operated channel expressed in T cells, mast cells, and various other tissues. CRAC channels regulate critical cellular processes such as gene expression, motility, and the secretion of inflammatory mediators. The identification of Orai1, a key subunit of the CRAC channel pore, and STIM1, the endoplasmic reticulum (ER) Ca2+ sensor, have provided the tools to illuminate the mechanisms of regulation and the pore properties of CRAC channels. Recent evidence indicates that the activation of CRAC channels by store depletion involves a coordinated series of steps, which include the redistributions of STIM1 and Orai1, direct physical interactions between these proteins, and conformational changes in Orai1, culm... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782848 Wed, 09 Sep 2009 23:00:00 +0100 2782848 http://www.medworm.com/index.php?rid=2782847&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00816.x Summary: For more than 25 years, it has been widely appreciated that Ca2+ influx is essential to trigger T-lymphocyte activation. Patch clamp analysis, molecular identification, and functional studies using blockers and genetic manipulation have shown that a unique contingent of ion channels orchestrates the initiation, intensity, and duration of the Ca2+ signal. Five distinct types of ion channels [ndash] Kv1.3, KCa3.1, Orai1+ stromal interacting molecule 1 (STIM1) [Ca2+-release activating Ca2+ (CRAC) channel], TRPM7, and Clswell[ndash] comprise a network that performs functions vital for ongoing cellular homeostasis and for T-cell activation, offering potential targets for immunomodulation. Most recently, the roles of STIM1 and Orai1 have been revealed in triggering and forming the CRAC ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782847 Wed, 09 Sep 2009 23:00:00 +0100 2782847 http://www.medworm.com/index.php?rid=2782846&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00808.x Summary: Mast cells are integral members of the immune system. Upon activation by a rise in cytoplasmic Ca2+, they release a battery of paracrine signals, chemokines, and cytokines, which help sculpt the subsequent immune response. Ca2+ entry through store-operated Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane is central for driving most of these responses. The molecular basis of the CRAC channel has been identified, with Orai1 forming the channel pore. Recent work has revealed that a range of mast cell responses are activated by spatially restricted Ca2+ signals just below the plasma membrane. These Ca2+ microdomains can activate cytosolic enzymes, leading to the generation of intracellular messengers as well as proinflammatory molecules like LTC4. In this review, we ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782846 Wed, 09 Sep 2009 23:00:00 +0100 2782846 http://www.medworm.com/index.php?rid=2782845&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00807.x Summary: Inositol-1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that are regulated by IP3 and Ca2+ and are modulated by many additional signals. These properties allow them to initiate and, via Ca2+-induced Ca2+ release, regeneratively propagate Ca2+ signals evoked by receptors that stimulate formation of IP3. The ubiquitous expression of IP3R highlights their importance, but it also presents problems when attempting to resolve the behavior of defined IP3R. DT40 cells are a pre-B-lymphocyte cell line in which high rates of homologous recombination afford unrivalled opportunities to disrupt endogenous genes. DT40-knockout cells with both alleles of each of the three IP3R genes disrupted provide the only null-background for analysis of homogenous recombinant IP3R. We ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782845 Wed, 09 Sep 2009 23:00:00 +0100 2782845 http://www.medworm.com/index.php?rid=2782844&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00810.x Summary: Rapid to moderately rapid changes in intracellular Ca2+ concentration, or Ca2+ signals, control a variety of critical cellular functions in the immune system. These signals are comprised of Ca2+ release from intracellular stores coordinated with Ca2+ influx across the plasma membrane. The most common mechanisms by which these two modes of signaling occur is through inositol 1,4,5-trisphosphate (IP3)-induced release of Ca2+ from the endoplasmic reticulum (ER) and store-operated Ca2+ entry across the plasma membrane. The latter process was postulated over 20 years ago, and in just the past few years, the key molecular players have been discovered: STIM proteins serve as sensors of Ca2+ within the ER which communicate with and activate plasma membrane store-operated channels composed... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782844 Wed, 09 Sep 2009 23:00:00 +0100 2782844 http://www.medworm.com/index.php?rid=2782843&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00823.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2782843 Mon, 31 Aug 2009 23:00:00 +0100 2782843 http://www.medworm.com/index.php?rid=2553282&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00800.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553282 Tue, 30 Jun 2009 07:58:03 +0100 2553282 http://www.medworm.com/index.php?rid=2553298&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00799.x Summary: Parasitic infections regulate/alter host immune responses. Among parasitic infections, helminth infection often leads to systemic immune suppression or anergy. Helminth infection or helminth extracts drive CD4+ T-helper (Th) cell responses towards Th2 type and activate antigen-presenting cells (APCs) such that these cells express an anti-inflammatory phenotype. Among the myriad molecules present on or secreted by helminth parasites, glycans have been shown to be key in inducing Th2-type and anti-inflammatory immune responses. The majority of studies on immune modulatory helminth glycans have focused on Lacto-N-fucopentaose III and LewisX. When presented as glycol-conjugates, with multiple copies of the sugars conjugated to a carrier molecule, these compounds activate APCs, inducin... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553298 Sun, 28 Jun 2009 23:00:00 +0100 2553298 http://www.medworm.com/index.php?rid=2553297&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00796.x Summary: Basal, activation, and arrest signaling in T cells determines survival, coordinates responses to pathogens, and, when dysregulated, leads to loss of self-tolerance and autoimmunity. At the T-cell surface, transmembrane glycoproteins interact with galectins via their N-glycans, forming a molecular lattice that regulates membrane localization, clustering, and endocytosis of surface receptors. Galectin[ndash]T-cell receptor (TCR) binding prevents ligand-independent TCR signaling via Lck by blocking spontaneous clustering and CD4-Lck recruitment to TCR, and in turn F-actin transfer of TCR/CD4-Lck complexes to membrane microdomains. Peptide[ndash]major histocompatibility complexes overcome galectin[ndash]TCR binding to promote TCR clustering and signaling by Lck at the immune synapse. ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553297 Sun, 28 Jun 2009 23:00:00 +0100 2553297 http://www.medworm.com/index.php?rid=2553296&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00803.x Summary: The lymphatic system is best known for draining interstitial fluid from the tissues and returning it to the blood circulation. However, the lymphatic system also provides the means for immune surveillance in the immune system, acting as conduits that convey soluble antigens and antigen-presenting cells from the tissues to the lymph nodes, where primary lymphocyte responses are generated. One macromolecule that potentially unites these two functions is the large extracellular matrix glycosaminoglycan hyaluronan (HA), a chemically simple copolymer of GlcNAc and GlcUA that fulfills a diversity of functions from danger signal to adhesive substratum, depending upon chain length and particular interaction with its many different binding proteins and a small but important group of recept... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553296 Sun, 28 Jun 2009 23:00:00 +0100 2553296 http://www.medworm.com/index.php?rid=2553295&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00791.x Summary: Notch signaling is required for the development of all T cells and marginal zone (MZ) B cells. Specific roles in T- and B-cell differentiation have been identified for different Notch receptors, the canonical Delta-like (Dll) and Jagged (Jag) Notch ligands, and downstream effectors of Notch signaling. Notch receptors and ligands are post-translationally modified by the addition of glycans to extracellular domain epidermal growth factor-like (EGF) repeats. The O-fucose glycans of Notch cell-autonomously modulate Notch[ndash]ligand interactions and the strength of Notch signaling. These glycans are initiated by protein O-fucosyltransferase 1 (Pofut1), and elongated by the transfer of N-acetylglucosamine (GlcNAc) to the fucose by [beta]1,3GlcNAc-transferases termed lunatic, manic, or... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553295 Sun, 28 Jun 2009 23:00:00 +0100 2553295 http://www.medworm.com/index.php?rid=2553294&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00802.x Summary: Most T lymphocytes recognize peptide antigens bound to or presented by molecules encoded in the major histocompatibility complex (MHC). The CD1 family of antigen-presenting molecules is related to the MHC-encoded molecules, but CD1 proteins present lipid antigens, mostly glycolipids. Here we review T-lymphocyte recognition of glycolipids, with particular emphasis on the subpopulation known as natural killer T (NKT) cells. NKT cells influence many immune responses, they have a T-cell antigen receptor (TCR) that is restricted in diversity, and they share properties with cells of the innate immune system. NKT cells recognize antigens presented by CD1d with hexose sugars in [alpha]-linkage to lipids, although other, related antigens are known. The hydrophobic alkyl chains are buried i... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553294 Sun, 28 Jun 2009 23:00:00 +0100 2553294 http://www.medworm.com/index.php?rid=2553293&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00790.x Summary: The glycocalyx is a glycan layer found on the surfaces of host cells as well as microorganisms and enveloped virus. Its thickness may easily exceed 50 nm. The glycocalyx does not only serve as a physical protective barrier but also contains various structurally different glycans, which provide cell- or microorganism-specific 'glycoinformation'. This information is decoded by host glycan-binding proteins, lectins. The roles of lectins in innate immunity are well established, as exemplified by collectins, dectin-1, and dendritic cell (DC)-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). These mammalian lectins are synthesized in the secretory pathway and presented on the cell surface to bind to specific glycan 'epitopes'. As they recognize non-self glycans... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553293 Sun, 28 Jun 2009 23:00:00 +0100 2553293 http://www.medworm.com/index.php?rid=2553292&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00794.x Summary: Galectin-3 is a [beta]-galactoside-binding animal lectin of appro- ximately 30 kDa and is evolutionarily highly conserved. Galectin-3 is promiscuous, its localization within the tissue micro-environment may be extracellular, cytoplasmic, or nuclear, and it has a concentration-dependent ability to be monomeric or form oligomers. These properties impart great flexibility on galectin-3 as a specific regulator of many biological systems including inflammation. For example, in acute tissue damage galectin-3 is a key component in the host defense against microbes such as Streptococcus pneumoniae. However, if tissue injury becomes repetitive galectin-3 also appears to be intimately involved in the transition to chronic inflammation, facilitating the walling off of tissue injury with fibr... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553292 Sun, 28 Jun 2009 23:00:00 +0100 2553292 http://www.medworm.com/index.php?rid=2553291&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00787.x Summary: The immune system has evolved sophisticated mechanisms composed of several checkpoints and fail-safe processes that enable it to orchestrate innate and adaptive immunity, while at the same time limiting aberrant or unfaithful T-cell function. These multiple regulatory pathways take place during the entire life-span of T cells including T-cell development, homing, activation, and differentiation. Galectin-1, an endogenous glycan-binding protein widely expressed at sites of inflammation and tumor growth, controls a diversity of immune cell processes, acting either extracellularly through specific binding to cell surface glycan structures or intracellularly through modulation of pathways that remain largely unexplored. In this review, we highlight the discoveries that have led to our... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553291 Sun, 28 Jun 2009 23:00:00 +0100 2553291 http://www.medworm.com/index.php?rid=2553290&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00801.x Summary: Siglecs (sialic acid-binding immunoglobulin-like lectins) are sialic acid-binding proteins, which are expressed on many cell types of the immune system. B cells express two members of the Siglec family, CD22 (Siglec-2) and Siglec-G, both of which have been shown to inhibit B-cell signaling. CD22 recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 (SHP-1) to immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and inhibits B-cell receptor (BCR)-induced Ca2+ signaling on normal B cells. CD22 interacts specifically with ligands carrying [alpha]2[ndash]6-linked sialic acids. Interaction with these ligands in cis regulates the association of CD22 with the BCR and thereby modulates the inhibitory function of CD22. Interaction of CD22 to ligands in trans c... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553290 Sun, 28 Jun 2009 23:00:00 +0100 2553290 http://www.medworm.com/index.php?rid=2553289&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00798.x Summary: Galectin-3 is absent in resting CD4+ and CD8+ T cells but is inducible by various stimuli. These include viral transactivating factors, T-cell receptor (TCR) ligation, and calcium ionophores. In addition, galectin-3 is constitutively expressed in human regulatory T cells and CD4+ memory T cells. Galectin-3 exerts extracellular functions because of its lectin activity and recognition of cell surface and extracellular matrix glycans. These include cell activation, adhesion, induction of apoptosis, and formation of lattices with cell surface glycoprotein receptors. Formation of lattices can result in restriction of receptor mobility and cause attenuation of receptor functions. Consistent with the presence of galectin-3 in intracellular locations, several functions have been described... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553289 Sun, 28 Jun 2009 23:00:00 +0100 2553289 http://www.medworm.com/index.php?rid=2553288&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00795.x Summary: Leukocyte recruitment encompasses cell adhesion and activation steps that enable circulating leukocytes to roll, arrest, and firmly adhere on the endothelial surface before they extravasate into distinct tissue locations. This complex sequence of events relies on adhesive interactions between surface structures on leukocytes and endothelial cells and also on signals generated during the cell[ndash]cell contacts. Cell surface glycans play a crucial role in leukocyte recruitment. Several glycosyltransferases such as [alpha]1,3 fucosyltransferases, [alpha]2,3 sialyltransferases, core 2 N-acetylglucosaminlytransferases, [beta]1,4 galactosyltransferases, and polypeptide N-acetylgalactosaminyltransferases have been implicated in the generation of functional selectin ligands that mediate... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553288 Sun, 28 Jun 2009 23:00:00 +0100 2553288 http://www.medworm.com/index.php?rid=2553287&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00797.x Summary: The substantial importance of P-selectin glycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initial identification as a selectin ligand. PSGL-1 seemed to be a relatively simple molecule with an extracellular mucin domain extended as a flexible rod, teleologically consistent with its primary role in tethering leukocytes to endothelial selectins. The rolling interaction between leukocyte and endothelium mediated by this selectin-PSGL-1 interaction requires branched O-glycan extensions on specific PSGL-1 amino acid residues. In some cells, such as neutrophils, the glycosyltransferases involved in formation of the O-glycans are constitutively expressed, while in other cells, such as T cells, they are expressed only after appropriate activation. ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553287 Sun, 28 Jun 2009 23:00:00 +0100 2553287 http://www.medworm.com/index.php?rid=2553286&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00792.x Summary: During evolution of the vertebrate cardiovascular system, the vast endothelial surface area associated with branching vascular networks mandated the development of molecular processes to efficiently and specifically recruit circulating sentinel host defense cells and tissue repair cells at localized sites of inflammation/tissue injury. The forces engendered by high-velocity blood flow commensurately required the evolution of specialized cell surface molecules capable of mediating shear-resistant endothelial adhesive interactions, thus literally capturing relevant cells from the blood stream onto the target endothelial surface and permitting subsequent extravasation. The principal effectors of these shear-resistant binding interactions comprise a family of C-type lectins known as '... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553286 Sun, 28 Jun 2009 23:00:00 +0100 2553286 http://www.medworm.com/index.php?rid=2553285&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00793.x Summary: [beta]-glucans are recognized by the innate immune system. This recognition plays important roles in host defense and presents specific opportunities for clinical modulation of the host immune response. Neutrophils, macrophages, and dendritic cells among others express several receptors capable of recognizing [beta]-glucan in its various forms. This review explores what is currently known about [beta]-glucan recognition and how this recognition stimulates immune responses. Special emphasis is placed on Dectin-1, as we know the most about how this key [beta]-glucan receptor translates recognition into intracellular signaling, stimulates cellular responses, and participates in orchestrating the adaptive immune response. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553285 Sun, 28 Jun 2009 23:00:00 +0100 2553285 http://www.medworm.com/index.php?rid=2553284&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00786.x Summary: C-type lectin receptors (CLRs) have long been known as pattern-recognition receptors implicated in the recognition of pathogens by the innate immune system. However, evidence is accumulating that many CLRs are also able to recognize endogenous 'self' ligands and that this recognition event often plays an important role in immune homeostasis. In the present review, we focus on the human and mouse CLRs for which endogenous ligands have been described. Special attention is given to the signaling events initiated upon recognition of the self ligand and the regulation of glycosylation as a switch modulating CLR recognition, and therefore, immune homeostasis. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553284 Sun, 28 Jun 2009 23:00:00 +0100 2553284 http://www.medworm.com/index.php?rid=2553283&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00789.x Summary: Innate immunity is the earliest response to invading microbes and acts to contain infection in the first minutes to hours of challenge. Unlike adaptive immunity that relies upon clonal expansion of cells that emerge days after antigenic challenge, the innate immune response is immediate. Soluble mediators, including complement components and the mannose binding lectin (MBL) make an important contribution to innate immune protection and work along with epithelial barriers, cellular defenses such as phagocytosis, and pattern-recognition receptors that trigger pro-inflammatory signaling cascades. These four aspects of the innate immune system act in concert to protect from pathogen invasion. Our work has focused on understanding the protection provided by this complex defense system ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2553283 Sun, 28 Jun 2009 23:00:00 +0100 2553283 http://www.medworm.com/index.php?rid=2529697&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00784.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529697 Thu, 30 Apr 2009 23:00:00 +0100 2529697 http://www.medworm.com/index.php?rid=2359315&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00025 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359315 Fri, 24 Apr 2009 08:13:48 +0100 2359315 http://www.medworm.com/index.php?rid=2359314&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00024 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359314 Fri, 24 Apr 2009 08:13:48 +0100 2359314 http://www.medworm.com/index.php?rid=2359313&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00023 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359313 Fri, 24 Apr 2009 08:13:48 +0100 2359313 http://www.medworm.com/index.php?rid=2359312&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00022 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359312 Fri, 24 Apr 2009 08:13:48 +0100 2359312 http://www.medworm.com/index.php?rid=2359311&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00021 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359311 Fri, 24 Apr 2009 08:13:48 +0100 2359311 http://www.medworm.com/index.php?rid=2359310&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00020 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359310 Fri, 24 Apr 2009 08:13:48 +0100 2359310 http://www.medworm.com/index.php?rid=2359309&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00019 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359309 Fri, 24 Apr 2009 08:13:48 +0100 2359309 http://www.medworm.com/index.php?rid=2359308&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00018 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359308 Fri, 24 Apr 2009 08:13:48 +0100 2359308 http://www.medworm.com/index.php?rid=2359307&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00017 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359307 Fri, 24 Apr 2009 08:13:48 +0100 2359307 http://www.medworm.com/index.php?rid=2359306&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00016 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359306 Fri, 24 Apr 2009 08:13:48 +0100 2359306 http://www.medworm.com/index.php?rid=2359305&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00015 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359305 Fri, 24 Apr 2009 08:13:48 +0100 2359305 http://www.medworm.com/index.php?rid=2359304&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00014 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359304 Fri, 24 Apr 2009 08:13:48 +0100 2359304 http://www.medworm.com/index.php?rid=2359303&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00013 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359303 Fri, 24 Apr 2009 08:13:48 +0100 2359303 http://www.medworm.com/index.php?rid=2359302&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00012 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359302 Fri, 24 Apr 2009 08:13:48 +0100 2359302 http://www.medworm.com/index.php?rid=2359301&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00011 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359301 Fri, 24 Apr 2009 08:13:48 +0100 2359301 http://www.medworm.com/index.php?rid=2359300&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00010 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359300 Fri, 24 Apr 2009 08:13:48 +0100 2359300 http://www.medworm.com/index.php?rid=2359299&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00009 (Source: Immunological Reviews) Immunological Reviews journals 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http://www.medworm.com/rss/comments.php?id=2359296 Fri, 24 Apr 2009 08:13:48 +0100 2359296 http://www.medworm.com/index.php?rid=2359295&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00005 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359295 Fri, 24 Apr 2009 08:13:48 +0100 2359295 http://www.medworm.com/index.php?rid=2359294&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00004 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359294 Fri, 24 Apr 2009 08:13:48 +0100 2359294 http://www.medworm.com/index.php?rid=2359293&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00003 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359293 Fri, 24 Apr 2009 08:13:48 +0100 2359293 http://www.medworm.com/index.php?rid=2359292&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00002 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359292 Fri, 24 Apr 2009 08:13:48 +0100 2359292 http://www.medworm.com/index.php?rid=2359291&cid=s_33160_3_f&fid=33906&url=http%3A%2F%2Fwww.ingentaconnect.com%2Fcontent%2Fmksg%2Fimr%2F2009%2F00000229%2F00000001%2Fart00001 (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2359291 Fri, 24 Apr 2009 08:13:48 +0100 2359291 http://www.medworm.com/index.php?rid=2529721&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00788.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529721 Mon, 20 Apr 2009 23:00:00 +0100 2529721 http://www.medworm.com/index.php?rid=2529720&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00785.x (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529720 Mon, 20 Apr 2009 23:00:00 +0100 2529720 http://www.medworm.com/index.php?rid=2529719&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00778.x Summary: Costimulatory receptors and ligands trigger the signaling pathways that are responsible for modulating the strength, course, and duration of an immune response. High-resolution structures have provided invaluable mechanistic insights by defining the chemical and physical features underlying costimulatory receptor:ligand specificity, affinity, oligomeric state, and valency. Furthermore, these structures revealed general architectural features that are important for the integration of these interactions and their associated signaling pathways into overall cellular physiology. Recent technological advances in structural biology promise unprecedented opportunities for furthering our understanding of the structural features and mechanisms that govern costimulation. In this review, we h... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529719 Mon, 20 Apr 2009 23:00:00 +0100 2529719 http://www.medworm.com/index.php?rid=2529718&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00773.x Summary: Pro-inflammatory CD4+ T-cell-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes, are hypothesized to be initiated and maintained by activated antigen-presenting cells presenting self antigen to self-reactive interferon-[gamma] and interleukin-17-producing CD4+ T-helper (Th) type 1/Th17 cells. To date, the majority of Food and Drug Administration-approved therapies for autoimmune disease primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop both therapies that inhibit/eliminate activated autoreactive cells as well as antigen-specific treatments, which allow for the directed blockade of the deleterious effects of self-reactive immune cell function. According to the two-signal hypot... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529718 Mon, 20 Apr 2009 23:00:00 +0100 2529718 http://www.medworm.com/index.php?rid=2529717&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00777.x Summary: The basis for susceptibility to common autoimmune diseases is a complex interplay between multiple genetic and environmental risk factors. We have now entered a new generation of genetic study designs which has not only furthered our understanding of the individual mechanisms involved in the common human autoimmune diseases but also has pointed towards common pathways. In this review we focus on costimulatory mechanisms with the most convincing association results in large collections of patients and control subjects. These include the genes encoding cytotoxic T-lymphocyte antigen-4, CD58, CD40, inducible T-cell costimulator ligand, CD244, CD226, tumor necrosis factor (TNF) (ligand) superfamily member 4, TNF superfamily member 15, and programmed cell death 1. The unbiased genome-w... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529717 Mon, 20 Apr 2009 23:00:00 +0100 2529717 http://www.medworm.com/index.php?rid=2529716&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00780.x Summary: This volume covers many topics in the field of T-cell costimulation. The need for such a volume is testament to the growth of the field. From its beginning as a concept in the 1980s, we have now progressed to the point where many molecules now have functionally defined roles in T-cell costimulation. In addition, the field has progressed 'from bench to bedside'. Abatacept [cytotoxic T-lymphocyte antigen-4 (CTLA-4)-immunoglobulin (Ig) (CTLA-4-Ig)], an inhibitor of CD28-mediated T-cell costimulation, was approved for the treatment of moderate-to-severe rheumatoid arthritis in 2006 by the Food and Drug Administration and in 2007 by the European Medicines Agency. This chapter first presents a personal historical perspective on the early basic studies on the elucidation of the CD28/B7 T... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529716 Mon, 20 Apr 2009 23:00:00 +0100 2529716 http://www.medworm.com/index.php?rid=2529715&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00776.x Summary: As the recognition that costimulatory signals are critical for optimal T-cell activation, proliferation, and differentiation, there has been an explosion in the study of costimulatory molecules and their roles in enhancing anti-donor T-cell responses following transplantation. Here, we focus on the bench-to-beside translation of blocking agents designed to target three critical costimulatory pathways: the CD28/CD80/CD86 pathway, the CD154/CD40 pathway, and the lymphocyte function associated antigen-1/intercellular adhesion molecule pathway. While blockade of each of these pathways proved promising in inhibiting donor-reactive T-cell responses and promoting long-term graft survival in murine models of transplantation, the progression of development of therapeutic agents to block th... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529715 Mon, 20 Apr 2009 23:00:00 +0100 2529715 http://www.medworm.com/index.php?rid=2529714&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00781.x Summary: T cells are central to graft rejection, and therefore preventing T cells from recognizing and destroying allografts remains an important area of transplant research. However, T cells are also required for transplant tolerance; a subset can enforce a state of tolerance by functioning as regulatory cells. As both rejection and regulation directed against alloantigens require T-cell activation, costimulatory molecules undoubtedly play an important role in regulating both processes and ultimately the fate of the allograft. However, costimulation involves an incredibly complex array of interactions that may act contemporaneously or at different times; these interactions can have additive or opposing effects on T-cell activation or differentiation. While some costimulatory molecules med... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529714 Mon, 20 Apr 2009 23:00:00 +0100 2529714 http://www.medworm.com/index.php?rid=2529713&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00772.x Summary: The T-cell immunoglobulin domain and mucin domain (TIM) family, including TIM-1, TIM-2, TIM-3, and TIM-4, is a relatively newly described group of molecules with a conserved structure and important immunological functions, including T-cell activation, induction of T-cell apoptosis and T-cell tolerance, and the clearance of apoptotic cells. TIM-1 costimulates T-cell activation and enhances cytokine production. In humans, TIM-1 also serves as a susceptibility gene for allergy and asthma. TIM-3, expressed on T cells and dendritic cells, regulates T-cell apoptosis and immune tolerance. By contrast, TIM-4, which is expressed primarily on antigen-presenting cells and which is a receptor for phosphatidylserine, regulates T-cell activation and tolerance, in part by mediating the uptake an... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529713 Mon, 20 Apr 2009 23:00:00 +0100 2529713 http://www.medworm.com/index.php?rid=2529712&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00783.x Summary: CD160 is a newly identified ligand for HVEM (herpes virus entry mediator). Previously identified HVEM ligands include BTLA (B- and T-lymphocyte attenuator), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes) and LT[alpha] (lymphotoxin-[alpha]). The binding of LIGHT or LT[alpha] to HVEM delivers a costimulatory signal, whereas the binding of BTLA or CD160 to HVEM delivers a coinhibitory signal. Thus, HVEM is a bidirectional switch regulating T-cell activation in a costimulatory or coinhibitory fashion whose outcome depends on the ligand engaged. The cysteine-rich domain 1 (CRD1) of HVEM is essential for the binding of coinhibitory ligands CD160 and BTLA but not costimulatory ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529712 Mon, 20 Apr 2009 23:00:00 +0100 2529712 http://www.medworm.com/index.php?rid=2529711&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00762.x Summary: LIGHT (homologous to lymphotoxins, inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator, a receptor expressed on T lymphocytes) is a member of the tumor necrosis factor superfamily that contributes to the regulation of immune responses. LIGHT can influence T-cell activation both directly and indirectly by engagement of various receptors that are expressed on T cells and on other types of cells. LIGHT, LIGHT receptors, and their related binding partners constitute a complicated molecular network in the regulation of various processes. The molecular cross-talk among LIGHT and its related molecules presents challenges and opportunities for us to study and to understand the full extent of the LIGHT function. Previous research from genetic and f... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529711 Mon, 20 Apr 2009 23:00:00 +0100 2529711 http://www.medworm.com/index.php?rid=2529710&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00774.x Summary: After binding its natural ligand cluster of differentiation 70 (CD70), CD27, a tumor necrosis factor receptor (TNFR)-associated factor-binding member of the TNFR family, regulates cellular activity in subsets of T, B, and natural killer cells as well as hematopoietic progenitor cells. In normal immune responses, CD27 signaling appears to be limited predominantly by the restricted expression of CD70, which is only transiently expressed by cells of the immune system upon activation. Studies performed in CD27-deficient and CD70-transgenic mice have defined a non-redundant role of this receptor[ndash]ligand pair in shaping adaptive T-cell responses. Moreover, adjuvant properties of CD70 have been exploited for the design of anti-cancer vaccines. However, continuous CD27[ndash]CD70 int... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529710 Mon, 20 Apr 2009 23:00:00 +0100 2529710 http://www.medworm.com/index.php?rid=2529709&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00765.x Summary: The tumor necrosis factor receptor family member 4-1BB plays a key role in the survival of activated and memory CD8+ T cells. Depending on the disease model, 4-1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4-1BB to prolong the immune response when pathogens take longer to clear. The expression of 4-1BB on diverse cell types, evidence for bidirectional as well as receptor-independent signaling by 4-1BBL, the unexpected hyperproliferation of 4-1BB-deficient T cells, and complex effects of agonistic an... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529709 Mon, 20 Apr 2009 23:00:00 +0100 2529709 http://www.medworm.com/index.php?rid=2529708&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00766.x Summary: OX40 (CD134) and its binding partner, OX40L (CD252), are members of the tumor necrosis factor receptor/tumor necrosis factor superfamily and are expressed on activated CD4+ and CD8+ T cells as well as on a number of other lymphoid and non-lymphoid cells. Costimulatory signals from OX40 to a conventional T cell promote division and survival, augmenting the clonal expansion of effector and memory populations as they are being generated to antigen. OX40 additionally suppresses the differentiation and activity of T-regulatory cells, further amplifying this process. OX40 and OX40L also regulate cytokine production from T cells, antigen-presenting cells, natural killer cells, and natural killer T cells, and modulate cytokine receptor signaling. In line with these important modulatory fu... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529708 Mon, 20 Apr 2009 23:00:00 +0100 2529708 http://www.medworm.com/index.php?rid=2529707&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00782.x Summary: During the generation of a successful adaptive immune response, multiple molecular signals are required. A primary signal is the binding of cognate antigen to an antigen receptor expressed by T and B lymphocytes. Multiple secondary signals involve the engagement of costimulatory molecules expressed by T and B lymphocytes with their respective ligands. Because of its essential role in immunity, one of the best characterized of the costimulatory molecules is the receptor CD40. This receptor, a member of the tumor necrosis factor receptor family, is expressed by B cells, professional antigen-presenting cells, as well as non-immune cells and tumors. CD40 binds its ligand CD40L, which is transiently expressed on T cells and other non-immune cells under inflammatory conditions. A wide s... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529707 Mon, 20 Apr 2009 23:00:00 +0100 2529707 http://www.medworm.com/index.php?rid=2529706&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00768.x Summary: B7-H3 and B7-H4 belong to a new class of immune regulatory molecules, which primarily execute their functions in peripheral tissues to fine tune immune responses in target organs. In normal circumstances, while the mRNA for both molecules is broadly distributed, tight control at the post-transcriptional level is imposed. Under a pathogenic environment, such as inflammation and cancer, the control is often aberrant. Upon engaging their receptors, these molecules regulate the immune response in positive or negative ways depending on the expression and type of cells bearing the receptors. Thus, manipulation of the expression of these molecules and/or their receptors may represent a realistic opportunity to fine tune immune responses and to design new immunotherapeutic approaches. (So... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529706 Mon, 20 Apr 2009 23:00:00 +0100 2529706 http://www.medworm.com/index.php?rid=2529705&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00771.x Summary: Despite the expression of antigens by tumor cells, spontaneous immune-mediated rejection of cancer seems to be a rare event. T-cell receptor engagement by peptide/major histocompatibility complexes constitutes the main signal for the activation of naive T cells but is not sufficient to initiate a productive generation and maintenance of effector cells. Full activation of T cells requires additional signals driven by costimulatory molecules present on activated antigen-presenting cells but rarely on tumors. Following the discovery of B7-1 (CD80), several other costimulatory molecules have been shown to contribute to T-cell activation and have relevance for improving anti-tumor immunity. Moreover, increasing the understanding of coinhibitory receptors has highlighted key additional ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529705 Mon, 20 Apr 2009 23:00:00 +0100 2529705 http://www.medworm.com/index.php?rid=2529704&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00767.x Summary: Programmed death-1 (PD-1) is a cell surface molecule that regulates the adaptive immune response. Engagement of PD-1 by its ligands PD-L1 or PD-L2 transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function. While a great deal is known concerning the biologic roles PD-1 plays in regulating the primary immune response and in T-cell exhaustion, comparatively little is known regarding how PD-1 ligation alters signaling pathways. PD-1 ligation is known to inhibit membrane-proximal T-cell signaling events, while ligation of the related inhibitory molecule cytotoxic T-lymphocyte antigen-4 appears to target more downstream signaling pathways. A major obstacle to an in-depth understanding of PD-1 signaling is the lack of physiologic models in which ... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529704 Mon, 20 Apr 2009 23:00:00 +0100 2529704 http://www.medworm.com/index.php?rid=2529703&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00764.x Summary: The identification of mutations in the inducible costimulator (ICOS) gene in nine patients with common variable immunodeficiency (CVID) was a major breakthrough. CVID is a complex, highly heterogeneous primary immunodeficiency disease, and the discovery of these mutations revealed a molecular basis. ICOS belongs to the CD28 family of costimulatory molecules and is expressed exclusively on activated T cells. It has at least three critical functions: germinal center formation, isotype class switching, and the development of memory B cells. The discovery of human ICOS deficiency showed that a monogenic disorder could account for the full spectrum of manifestations seen in childhood and adulthood-onset CVID, including autoimmune, inflammatory, and malignant disease complications, as w... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529703 Mon, 20 Apr 2009 23:00:00 +0100 2529703 http://www.medworm.com/index.php?rid=2529702&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00769.x Summary: In addition to signals from the T-cell receptor complex, it has been recognized for many years that a 'second' signal, most notably from CD28, is also important in T-cell activation. In the recent years, many new members of CD28 family as well as the molecules that share structural homology to CD28 ligands CD80 and CD86 have been discovered. Interestingly, some of these proteins function to dampen T-cell activation and regulate the induction of T-cell tolerance. Therefore, positive and negative costimulation are the two sides of the coin to fine tune T-cell receptor signaling to determine the outcome of T-cell receptor engagement-tolerance versus function. (Source: Immunological Reviews) Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529702 Mon, 20 Apr 2009 23:00:00 +0100 2529702 http://www.medworm.com/index.php?rid=2529701&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00763.x Summary: The generation of productive adaptive immune responses depends on the antigen-specific activation of T and B cells. The outcome of T-cell receptor engagement is influenced by signals from both positive and negative regulatory molecules that can either activate or inhibit T-cell function. CD28 and cytotoxic T-lymphocyte antigen-4 are the prototypical members of an immunoglobulin domain-containing protein family that play important roles in the control of T-cell responses against infection, cancer, and in autoimmune disease. Although the precise molecular details of their functions are still under active investigation, tumors and chronic pathogens seem to have exploited these pathways to achieve immune evasion. Furthermore, malfunction of the inhibitory arm of the immune response ap... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529701 Mon, 20 Apr 2009 23:00:00 +0100 2529701 http://www.medworm.com/index.php?rid=2529700&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00775.x Summary: Costimulation is a concept that goes back to the early 1980s when Lafferty and others hypothesized that cell surface and soluble molecules must exist that are essential for initiating immune responses subsequent to antigen exposure. The explosion in this field of research ensued as over a dozen molecules have been identified to function as second signals following T-cell receptor engagement. By 1994, it seemed clear that the most prominent costimulatory pathway CD28 and functionally related costimulatory molecules, such as CD154, were the major drivers of a positive immune response. Then the immunology world turned upside down. CD28 knockout mice, which were, in most cases, immunodeficient, led to increased autoimmunity when bred into the non-obese diabetic background. Another CD2... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529700 Mon, 20 Apr 2009 23:00:00 +0100 2529700 http://www.medworm.com/index.php?rid=2529699&cid=s_33160_3_f&fid=33160&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1600-065X.2009.00779.x Summary: T-cell activation requires contact between T cells and antigen-presenting cells (APCs) to bring T-cell receptors (TCRs) and major histocompatibility complex peptide (MHCp) together to the same complex. These complexes rearrange to form a concentric circular structure, the immunological synapse (IS). After the discovery of the IS, dynamic imaging technologies have revealed the details of the IS and provided important insights for T-cell activation. We have redefined a minimal unit of T-cell activation, the 'TCR microcluster', which recognizes MHCp, triggers an assembly of assorted molecules downstream of the TCR, and induces effective signaling from TCRs. The relationship between TCR signaling and costimulatory signaling was analyzed in terms of the TCR microcluster. CD28, the most... Immunological Reviews journals http://www.medworm.com/rss/comments.php?id=2529699 Mon, 20 Apr 2009 23:00:00 +0100 2529699