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• W2007694513 abstract "Historically, our studies of the immune system have concentrated on its activation for protection against pathogen invasion. With increasing awareness of the need to terminate immune responses, both from the standpoint of maintaining clonal equilibrium of the effector cells and limiting the extent of inflammatory tissue damage, immunologists have devoted more and more attention to the underlying mechanisms for inhibiting the immune response. One of the earliest insights into possible mechanisms for terminating immune responses derived from the observation that feedback by antibodies themselves could suppress ongoing antibody production to a specific immunogen (1). This phenomenon proved to be a special property of immunoglobulin G (IgG) antibodies, one requiring integrity of the Fc portion (2). The elucidation of Fc receptors and their ability to transmit the signal for inhibiting antigen activation of the antibody-producing cells came much later. In this issue, Daëron et al. (3) and Cady et al. (4) describe the characterization of the immunoreceptor tyrosine-based inhibition motif (ITIM) in the Fc receptor FcγRIIB. This inhibitory motif was identified following Reth's recognition of the immunoreceptor tyrosine-based activation motif (ITAM) in B-cell receptors (BCRs), T-cell receptors (TCRs), and Fc receptors with activating potential, such as FcγRIIA (5), and the present reviews emphasize the general rule that ITIM-bearing inhibitory receptors function in conjunction with activating receptors. A classic example of this dynamic relationship is the pairing of the ITIM-containing FcγRIIB with the BCR or activating Fc receptors on B cells, dendritic cells, monocytes, or mast cells. When they are brought together with a neighboring activating receptor that binds the same or a complementary ligand, the inhibitory receptor ITIMs are phosphorylated by Src-family tyrosine kinases to facilitate the recruitment of Src homology 2 (SH2) domain-containing phosphatases that in turn disable the activation signal components. The general principle of paired expression of activating and inhibitory receptors with related ligand binding holds for the regulation of a wide variety of cell types in addition to cells of the immune system. Daëron et al. (3) perform a phylogenetic analysis, which suggests that ITIM-containing receptor pairing with an ITAM-containing receptor is an ancient strategy. They trace the ITIM consensus sequences to the most primitive metazoans. Most of the currently defined inhibitory receptors preferentially recruit the tyrosine phosphatases SHP-1 and/or SHP-2, although slight ITIM sequence variations in the different inhibitory receptors may determine the alternative use of inositol or protein tyrosine phosphatases. FcγRIIB is the best example for the alternative use of the inositol phosphatase SHIP-1, and Cady et al. (4) discuss what is known about the determining factors for SHIP-1 versus SHP-1 usage. In this regard, the inhibition of cellular activation is much greater when the ITIMs recruit SHPs instead of SHIPs, although other more subtle variations may affect the degree of ITIM-mediated inhibition. The paired relationship of inhibitor and activating receptor expression is exemplified by the different types of Fc receptors, but this balanced relationship is also an important feature in the function of killer inhibitor receptors (KIRs), paired Ig-like receptors (PIRs), signal regulatory proteins (SIRPs), Ig-like transcripts (ILTs), myeloid-associated Ig-like receptors (MAIRs), and leukocyte mono-Ig-like receptors (LMRRs). Inhibitory receptors with ITIMs in their cytoplasmic domain play a dominant role in determining the function of natural killer (NK) cells, the effector immune cells that were discovered in mice and humans on the basis of their spontaneous ability to kill tumor or virus-infected cells. Reviews by the Moretta et al. (6), Long (7), Joncker and Raulet (8), and Barrow and Trowsdale (9) detail the extensive array of activating and inhibitory receptors used by NK cells to govern their cytotoxic activity, as well as to govern the functional status of other immune and non-immune system cells. Normally, NK cells are held in a dormant mode as a consequence of their inhibitory receptor recognition of major histocompatibility complex (MHC) class I molecules on neighboring cells. However, when MHC class I expression is downregulated by virus infection or on tumor cells, NK killing is triggered by the unopposed function of activating receptors on the NK cells, a concept that was first proposed in the ‘missing-self hypothesis’ of Karre et al. (10). In his review, Long (7) considers the mechanism by which KIRs function via SHP-mediated dephosphorylation of phosphotyrosine-dependent activation signals as a generic model for understanding how the ITIM-containing inhibitory receptors work. He notes that this basic operational mode extends to the CD94/NKG2A, programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), the B- and T-lymphocyte attenuator (BTLA) on T and B cells, the Ig-like receptor B (TIRB) on B and myeloid cells in mice, and leukocyte Ig-like receptors (LIR). Long suggests that SHP-1 targets for dephosphorylation of a single predominant component of the activation pathway, rather than targeting many signaling components in activation pathways. This model for a preferential SHP substrate suggests how ITIM-containing receptors may finely tune the regulation of activation signals, the challenge being to elaborate the molecular details of the initiation and propagation of inhibitory signals delivered by different ITIM-containing receptors in their natural physiological context. The many immunoglobulin superfamily (IgSF) genes of the extended leukocyte receptor complex (LCR) on chromosome 19g13.4 in humans are reviewed by Barrow and Trowsdale (9). Following their comprehensive review of this highly polymorphic complex of PIR genes, these authors present four models via which negative LRC regulators of cellular activation may (i) achieve direct inhibition of a cell expressing a classical inhibitory receptor, (ii) accomplish indirect inhibition when an effector cell response inhibits behavior of another cell, (iii) affect homeostasis in immune privilege sites like the brain, or (iv) adopt molecular hijack strategies that result in cellular inhibition. Joncker and Raulet (8) further address the complexity of the variable NK receptor repertoire. Noting that some NK cells fail to express any of the known inhibitory receptors for self MHC class I, they suggest the hyporesponsiveness of these NK cells is due to persistent overstimulation by neighboring cells. This environmental fine-tuning process is thought to determine the functional set-point of NK cells as a means for discriminating self from missing self, while at the same time endowing each NK cell with the highest responsive potential compatible with cell tolerance. The Moretta et al. review (6) describes how alloreactive NK cells may be used to prevent leukemic relapses by hematopoietic stem cell transplantation in adults with high-risk acute mylogenous leukemia, in children with acute lymphoblastoid leukemia or in patients with chemotherapy-refractory leukemia. Inhibitory T cells, famously having undergone name change from T-suppressor cells to T-regulatory (Treg) cells, have regained center stage following their definition on the basis of the expression of CD25 [interleukin-2 (IL-2) receptor α chain] and the forkhead box protein 3 (FOXP3) transcription factor (11). In the present volume, Smith and Popmihajlov (12) review evidence suggesting a negative feedback role for IL-2 in regulating T-cell responses. In their model, TCR ligation induces the production of IL-2 that in turn binds to its upregulated receptor, which then triggers the expression of FOXP3 as a negative transcriptional regulator that restricts IL-2 expression, thereby quenching the T-cell response. Peggs et al. (13) focus their review on intrinsic T-cell inhibitory pathways that play central roles in coordinating immune responses. Whereas the B7-1/B7-2 ligand pair on antigen-presenting cells serves to activate T cells through CD28 ligation, the ensuing CTLA-4 molecule expression by the activated T cells can competitively bind the B7 molecules to trigger cellular inhibition. The inhibition is achieved via CTLA-4 ITIM phosphorylation to recruit SHP-2 tyrosine phosphatase that then effectively disables the TCR signaling pathway to terminate the response. After reviewing information on the regulatory mechanisms used by the CD28/CTLA-4:B7-1/B7-2 receptor/ligand pairs and by the PD-1/PD-1L receptor/ligand pair, Allison et al. (13) describe the status of current strategies to block these interactions for the purpose of promoting tumor rejection or terminating chronic viral infections. Fife and Bluestone (14) contrast the roles of CTLA-4 and PD-1 in limiting T-cell autoreactivity and in mediating peripheral tolerance to self-antigens. They propose that CTLA-4 signals are required during the initiation of the immune response, whereas the PD-1 pathway acts later to limit T-cell activity. Both of these articles illustrate the precarious balance between beneficial T-cell responses and unchecked inflammatory immune responses. The complexities of regulating cell activation, proliferation, and differentiation through the use of different cell surface receptors, intracellular signaling components, and gene expression profiles vary as a function of the different stages in cellular differentiation. The intricacies of the complex progression schemes are perhaps best revealed in studies of the T- and B-cell differentiation pathways. Richards et al. (15) review currently available information on the signaling pathways that are initiated by ligation of the BCR, CD40, and Toll-like receptors to influence the fate of clonally diverse B cells. Within the context of an extensive company of signal-transducing molecules that act at different phases in the B-cell activation process, this review focuses on the promotion of BCR-induced cell cycle entry by the Bam 32 adapter protein versus the opposing effect of the secondary messenger super oxide. Noting that B-cell progression through the cell cycle is governed by caspase 6, Bim, and Bcl2, together with other regulators of cell survival versus cell death, they emphasize the potential for therapeutic drugs that could selectively target pathogenic B cells. Although best known for their antibody production and promotion of T-cell activation, B cells can serve other immunoregulatory functions. In this context, Bouaziz et al. (16) describe a novel subset of regulatory B cells that can downregulate immune responses in autoimmunity and inflammation models, such as experimental autoimmune encephalomyelitis, contact hypersensitivity, and non-obese diabetes in mice. They propose the name B10 for this numerically limited yet functionally potent subpopulation of regulatory B cells that are distinguishable by their expression of cell surface CD5 and high levels of CD1d and their production of the IL-10 inhibitory cytokine. While a comparable regulatory B cell has yet to be defined in humans, these authors point to suggestive evidence for their existence, the confirmation of which could lead to new strategies for treating autoimmune and inflammatory diseases. An influential group of transmembrane adapter proteins (TRAPs) function to fine-tune antigen receptor-mediated signals by organizing signaling complexes at the cell membrane. Among these, the linker for activation of T cells (LAT) is best known for its role in T-cell development and activation, although Simeoni et al. (17) note that LAT can also assemble inhibitory complexes to trigger negative feedback loops. They review evidence indicating that other TRAPs, including the SHP-2 interacting transmembrane adaptor protein (SIT), TCR interacting protein (TRIM), linker for activation of X cells (LAX), and non-T-cell activation linker (NTAL), all have fine-tuning inhibitory roles that collectively serve a crucial role in establishing tolerance. Moreover, their absence can lead to autoimmune disease. Engagement of the ubiquitously expressed adapter protein PAG can also serve an important regulatory role by negatively regulating Src kinases, Ras, and lipid raft mobility. PAG dysfunction can lead to T-cell malignancy. The Cbl family of ubiquitous ligases can serve as important negative regulators of immune responses by governing TCR, BCR, and coreceptor signaling. Huang and Gu (18) review the redundant roles of c-Cbl and Cbl-b in thymocyte development, in controlling the activation threshold, and CD28 costimulation for peripheral T cells, and in setting the BCR signaling threshold for normal B-cell maturation versus anergy induction. The phosphoinositide-3 kinase (PI3K) signaling pathway that is activated via ligation of the TCR, CD28, and common γ chain cytokine receptors for IL-2, -4, -7, and -15 serves to modulate T-cell activation and survival by promoting the production of the lipid second messenger PIP3. Buckler et al. (19) detail how the PI3K-opposing activity of the lipid phosphatase PTEN (phosphatase and tensin homolog) influences thymocyte selection and mature T-cell activation, thereby preventing autoimmune diseases and uncontrolled T-cell hyperplasia. They note that PTEN is a tumor suppressor gene, deletions or mutations of which are seen in up to 50% of tumors. Both of these articles suggest ways in which these signaling pathways could be modulated to clinical advantage in the treatment of autoimmunity and cancer. Diacylglycerol (DAG) and phosphatidic acid (PA) are important second messengers that are generated following the ligation of TCRs, BCRs, TLRs, FcɛRI, chemokine receptors, and many other receptors. Zhong et al. (20) describe the activity of the different diacylglycerol kinase family members in catalyzing phosphorylation of DAG to produce PA to regulate the development and function of T cells, mast cells, dendritic cells, and macrophages by activating multiple signaling cascades. The highly conserved suppressor of cytokine signaling (SOCS) proteins function as important downstream signaling components to negatively regulate activation and differentiation of macrophages, dendritic cells, and T cells. Dimitriou et al. (21) review new insights into the structure and function of the SOCS1 and SOCS2 proteins that help to explain their roles in maintenance of a coordinated balance between innate and adaptive immune responses. Mueller and Ahmed (22) review the influential roles that stromal cells and lymphoid tissue architecture serve in regulating immune responses. These authors emphasize the dynamic participation of lymphoid stromal cells, fibroblastic reticular cells, and follicular dendritic cells, through their production of cytokines, chemokines, and adhesion factors that govern migration, homeostasis, and survival of T, B, and antigen-presenting cells (22). They illustrate the dramatic changes in lymphoid stromal cells that occur during immune responses to alter the migration and localization of immune cells in lymphoid organs. While these changes downregulate the immune response to promote the resetting of clonal equilibrium, they may also contribute to the susceptibility to secondary infections that is seen following viral infections. In reading these informative reviews, one cannot help being impressed by the remarkable diversity of the interwoven mechanisms used to control the extent of immune responses for a healthy existence. Defects in virtually all of the known mechanisms for downregulating immune responses can lead to a variety of clinical disorders, including autoimmune diseases, malignancies, and chronic inflammation. Increasing knowledge of how the balance is maintained between activating and inhibitory pathways will undoubtedly lead to more refined means of intervention to modify immune system equilibrium for clinical advantage. These reviews also make clear that there is still much work left to do in order to reach this goal." @default.
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• W2007694513 title "Inhibition of immune cell function" @default.
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