Immunological Reviews
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Control of peripheral T‐cell tolerance and autoimmunity via the CTLA‐4 and PD‐1 pathways Summary: Classically, the CD28/cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and B7 families of cell surface molecules regulate complex signaling pathways that profoundly affect T‐cell responses. The recent identification and characterization of additional CD28 and B7 family members including programmed death‐1 (PD‐1), programmed death ligand‐1 (PD‐L1) (B7‐H1), and PD‐L2 (B7‐DC) has added to the complexity and greater appreciation of how surface molecules control T‐cell activation and peripheral tolerance. CD28/B7 interactions mediate co‐stimulation and significantly enhance peripheral T‐cell responses. CTLA‐4, in contrast, interacting with the same B7 molecules, results in decreased T‐lymphocyte activity and regulates the immune response. Similarly, PD‐1 interactions with PD‐L1 and PD‐L2 downmodulate T‐cell immune responses. Despite these similarities, the regulatory roles of the CTLA‐4 and PD‐1 pathways are distinct. This may be due, at least in part, to the differential expression patterns of the CTLA‐4 and PD‐1 ligands both temporally and spatially. This article examines the role of CTLA‐4 and PD‐1 in limiting autoreactivity and establishing peripheral self‐tolerance with the hypothesis that CTLA‐4 signals are required early in the lymph node during initiation of an immune response and PD‐1 pathways act late at the tissue sites to limit T‐cell activity.
Immunological Reviews - Tập 224 Số 1 - Trang 166-182 - 2008
A global approach to <scp>HIV</scp>‐1 vaccine development Summary A global human immunodeficiency virus‐1 (HIV ‐1) vaccine will have to elicit immune responses capable of providing protection against a tremendous diversity of HIV ‐1 variants. In this review, we first describe the current state of the HIV ‐1 vaccine field, outlining the immune responses that are desired in a global HIV ‐1 vaccine. In particular, we emphasize the likely importance of Env‐specific neutralizing and non‐neutralizing antibodies for protection against HIV ‐1 acquisition and the likely importance of effector Gag‐specific T lymphocytes for virologic control. We then highlight four strategies for developing a global HIV ‐1 vaccine. The first approach is to design specific vaccines for each geographic region that include antigens tailor‐made to match local circulating HIV ‐1 strains. The second approach is to design a vaccine that will elicit Env‐specific antibodies capable of broadly neutralizing all HIV ‐1 subtypes. The third approach is to design a vaccine that will elicit cellular immune responses that are focused on highly conserved HIV ‐1 sequences. The fourth approach is to design a vaccine to elicit highly diverse HIV ‐1‐specific responses. Finally, we emphasize the importance of conducting clinical efficacy trials as the only way to determine which strategies will provide optimal protection against HIV ‐1 in humans.
Immunological Reviews - Tập 254 Số 1 - Trang 295-304 - 2013
The C‐type lectin superfamily in the immune system Summary: Protein‐carbohydrate interactions serve multiple functions in the immune system. Many animal lectins (sugar‐binding proteins) mediate both pathogen recognition and cell‐cell interactions using structurally related Ca2+ ‐dependent carbohydrate‐recognition domains (C‐type CRDs). Pathogen recognition by soluble collections such as serum mannose‐binding protein and pulmonary surfactant proteins, and also the macrophage cell‐surface mannose receptor, is effected by binding of terminal monosaccharide residues characteristic of bacterial and fungal cell surfaces. The broad selectivity of the monosaccharide‐binding site and the geometrical arrangement of multiple CRDs in the intact lectins explains the ability of the proteins to mediate discrimination between self and non‐self. In contrast, the much narrower binding specificity of selectin cell adhesion molecules results from an extended binding site within a single CRD. Other proteins, particularly receptors on the surface of natural killer cells, contain C‐type lectin‐like domains (CTLDs) that are evolutionarily divergent from the C‐type lectins and which would be predicted to function through different mechanisms.
Immunological Reviews - Tập 163 Số 1 - Trang 19-34 - 1998
Regulation of Genome Rearrangement Events during Lymphocyte Differentiation
Immunological Reviews - Tập 89 Số 1 - Trang 5-30 - 1986
Neoplastic development in plasma cells Summary: An increasing number of model systems of plasma cell tumor (PCT) formation have been and are being developed. Discussed here are six models in mice and multiple myeloma (MM) in humans. Each model illustrates a unique set of biological factors. There are two general types of model systems: those that depend upon naturally arising mutagenic changes (pristane‐induced PCTs, 5TMM, and MM) and those that are associated with oncogenes (Eµ‐v‐abl), growth factors [interleukin‐6 (IL‐6)], and anti‐apoptotic factors (Bcl‐xL /Bcl‐2). PCTs develop in several special tissue microenvironments that provide essential cytokines (IL‐6) and cell–cell interactions. In mice, the activation and deregulation of c‐myc by chromosomal translocations is a major feature in many of the models. This mechanism is much less a factor in MM and the 5T model in mice. Genetically determined susceptibility is involved in many of the mouse models, but only a few genes have been implicated thus far.
Immunological Reviews - Tập 194 Số 1 - Trang 177-195 - 2003
From T‐cell activation signals to signaling control of anti‐cancer immunity Summary: The activation of resting T cells is crucial to most immune processes. Recognition of foreign antigen by T‐cell receptors has to be correctly translated into signal transduction events necessary for the induction of an effective immune response. In this review, we discuss the essential signals, molecules, and processes necessary to achieve full T‐cell activation. In addition to describing these key biological events, we also discuss how T‐cell receptor signaling may be harnessed to yield new therapeutic targets for a next generation of anti‐cancer drugs.
Immunological Reviews - Tập 220 Số 1 - Trang 151-168 - 2007
Innate immune memory: An evolutionary perspective Summary Over the last decades, there was increasing evidence for the presence of innate immune memory in living organisms. In this review, we compare the innate immune memory of various organisms with a focus on phylogenetics. We discuss the acquisition and molecular basis of immune memory and we describe the innate immune memory paradigm and its role in host defense during evolution. The molecular characterization of innate immunological memory in diverse organisms and host‐parasite systems reconciles mechanisms with phenomena and paves the way to molecular comprehension of innate immune memory. We also revise the traditional classification of innate and adaptive immunity in jawed vertebrates. We emphasize that innate immune responses have the capacity to be “primed” or “trained”, thereby exerting a yet unknown type of immunological memory upon re‐infection.
Immunological Reviews - Tập 283 Số 1 - Trang 21-40 - 2018
Activation‐induced cell death in T cells Summary: A properly functioning immune system is dependent on programmed cell death at virtually every stage of lymphocyte development and activity. This review addresses the phenomenon of activation‐induced cell death (AICD) in T lymphocytes, in which activation through the T‐cell receptor results in apoptosis. AICD can occur in a cell‐autonomous manner and is influenced by the nature of the initial T‐cell activation events. It plays essential roles in both central and peripheral deletion events involved in tolerance and homeostasis, although it is likely that different forms of AICD proceed via different mechanisms. For example, while AICD in peripheral T cells is often caused by the induction of expression of the death ligand, Fas ligand (CD95 ligand, FasL), it does not appear to be involved in AICD in thymocytes. This and other mechanisms of AICD are discussed. One emerging model that may complement other forms of AICD involves the inducible expression of FasL by nonlymphoid tissues in response to activated T lymphocytes. Induction of nonlymphoid FasL in this manner may serve as a sensing mechanism for immune cell infiltration, which contributes to peripheral deletion.
Immunological Reviews - Tập 193 Số 1 - Trang 70-81 - 2003
A New Approach to the Study of Human B Lymphocyte Function Using an Indirect Plaque Assay and a Direct B Cell Activator
Immunological Reviews - Tập 45 Số 1 - Trang 41-67 - 1979
Ecto‐phosphodiesterase/pyrophosphatase of lymphocytes and non‐lymphoid cells: structure and function of the PC‐1 family Summary: Many developmentally regulated membrane proteins of lymphocytes are ecto‐enzymes, with their active sites on the external surface of the cell. These enzymes commonly have peptidase, phosphodiesterase or nucleotidase activity. Their biological roles are just beginning to be discovered. Although their expression is usually associated with particular stages of lymphoid differentiation, the same gene products are often expressed on the surface of certain non‐lymphoid cell types outside the immune system, indicating that their functions cannot be unique to lymphocytes, nor can they be ubiquitous. The plasma cell membrane protein PC‐1 (phosphodiesterase I; EC 3.1.4.1/nucleotide pyrophosphatase; EC 3.6.1.9), which was one of the first serological markers for lymphocyte subsets to be discovered, is a typical example. Within the immune system, PC‐1 is confined to plasma cells, which represent about 0.1% of lymphocytes. However, PC‐1 is also expressed on cells of the distal convoluted tubule of the kidney, chondrocytes, osteoblasts, epididymis and hepatocytes. Recent work has shown that PC‐1 is a member of a multigene family of ecto‐phosphodiesterases that currently has two other members, PD‐1α (autotaxin) and PD‐1β (B10). Within this family, the extracellular domains are highly conserved, especially around the active site. In contrast, the transmembrane and cytopiasmic domains are highly divergent. Individual members of the ecto‐phosphodiesterase family have distinct patterns of distribution in different cell types, and even within the same cell. For example, PC‐1 is present only on the basolateral surface of hepatocytes, while B10 (PD‐1β) is confined to the apical surface. Analysis of conservation and differences in the sequence of their cytoplasmic tails may illuminate intracellular tar‐getting signals. Ecto‐phosphodiesterases may play a part in diverse activities in different tissues, including recycling of nucleotides. They may also regulate the concentration of pharmacologically active extracellular compounds such as adenosine or its derivatives and ceil motility. Some members may modulate local concentrations of pyrophosphate, and hence influence calcification in bone and cartilage.
Immunological Reviews - Tập 161 Số 1 - Trang 11-26 - 1998
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