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• W2736844309 abstract "Howard Hughes Medical Institute Department of Medicine llniversity of California, San Francisco San Francisco, California 94143 tHoward Hughes Medical Institute Department of Microbiology and Immunology llniversity of California, San Francicso San Francisco, California 94143 Introduction E3 and T lymphocytes, the antigen-specific cells of the im- rnune system, are generally quiescent and require antigen stimulation to progress from the Go stage of the cell cycle. Specific responses to pathogens or foreign substances require that receptors on these cells recognize the antigen as well as initiate a series of signal transduction events. These signals are fundamental both in developmental de- c:isions and in the initiation of immune responses by B and T cells. Here we focus on recent progress in understanding how T cell antigen receptors (TCRs) initiate signal trans- cluction events that lead to cellular responses. Where ap- propriate and possible, parallels and contrasts with the B cell system will be discussed. T and B cells have structurally different oligomeric anti- gen receptors that recognize fundamentally distinct forms of antigens. B cells function to protect the host from extra- cellular pathogens. Their receptors typically recognize na- tive or denatured forms of proteins or carbohydrates in soluble, particulate, or cell-bound form. In contrast, the T cell system protects the host against intracellular patho- gens. TCRs recognize proteolytically processed short (,B - 15 residues) peptide antigens bound to self major his- tlocompatibility complex (MHC) molecules on the surface of an antigen-presenting cell. Thus, B and T cells recog- nize distinct forms of antigen using very different recep- tlors. Remarkably, the signal transduction events that re- sult from the interaction of their antigen receptors with antigen are quite similar. In addition to the antigen receptors, other molecules contribute to cell activation: first, by functioning as core- ceptors (e.g., CD4, CD8, CD19/CD21); second, by in- creasing the avidity of the interaction with antigen or the antigen-presenting cell (e.g., LFA-1); or, third, by inducing separate signal transduction events that influence the cel- lular response (e.g., CD28, CD40). Coreceptors, such as CD4 or CD8 in T cells or CD19/CD21 in B cells, are of particular interest in the context of antigen receptor signal transduction, since they directly contribute to the forma- tion of the complex between the antigen receptor and the antigen complex, thereby increasing the sensitivity of the interaction. The coreceptors also contribute to the initia- tion of signals, as we will discuss below. Protein-tyrosine phosphorylation is important in the initi- ation of cellular responses by antigen receptors on either E3 or T cells. Neither the TCR nor the B cell antigen receptor (BCR) has intrinsic PTK activity. Both appear to activate cytoplasmic PTKs, although at least one tyrosine phospha- tase, CD45, is also important in regulating antigen recep- tor-induced signal transduction. Members of two distinct classes of PTKs, the Src family and Syk/ZAP-70 family, have been implicated in TCR and BCR signal trans- duction. These distinct PTKs interact with the TCR and BCR as well with each other. The events downstream of protein-tyrosine phosphory- lation following TCR or BCR stimulation include the activa- tion of the phosphatidylinositol pathway, activation of Ras, and activation of several serinelthreonine protein kinases and phosphatases. These events have been causally re- lated to a variety of responses, of which the best character- ized is the transcriptional induction of the interleukin 2 (IL-2) gene in T cells. Our understanding of the detailed intermolecular connections between the early events and later cellular responses is rapidly evolving. The interpretation of the signal transduced by the anti- gen receptor may differ, depending on the developmental stage of the responding cell or on the cellular context of antigen recognition. For instance, signal transduction by the TCR in developing thymocytes can lead either to pro- grammed cell death (apoptosis) or to selection, depending on the antigen specificity of the TCR. In mature T cells, TCR recognition of antigen can lead either to differentia- tion and proliferation or to a long-lived state of unrespon- siveness (anergy), depending on whether appropriate sec- ond (costimulatory) signals are provided by molecules such as CD28, which interacts with ligands on antigen- presenting cells. This review will focus on the biochemical events induced by the antigen receptors, whereas other reviews in this issue will address the different responses that lymphocytes can make to these signals, depending on developmental and cellular contexts. T and B Ceil Antigen Receptors The ability to recognize a vast array of pathogens and foreign substances is the responsibility of antigen-specific receptors expressed on T and B cells. Both the BCR and TCR have separate antigen-binding and signal transduc- tion subunits (Figure 1). The antigen-binding subunits can- not be expressed independently at the plasma membrane, but must form a complex with the invariant chains respon- sible for receptor signaling function (Weiss, 1991). The TCR Ti subunit is noncovalentlyassociated with the CD36, CD~E, and CD3y chains and a i chain-containing dimer (which may consist of homodimers or heterodimers with q or FcERI~ chains). It is believed that each Ti subunit associated with a" @default.
• W2736844309 created "2017-07-31" @default.
• W2736844309 creator A5050836076 @default.
• W2736844309 creator A5087707385 @default.
• W2736844309 date "1994-01-01" @default.
• W2736844309 modified "2023-09-27" @default.
• W2736844309 title "Signal Transduction by Lymphocyte Antigen Receptors Review" @default.
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