Function of TCR invariant subunits

A critical early finding was that monoclonal antibodies to CD3, most of which recognize the CD3€ chain, were able to activate resting T cells in the presence of monocytes bearing appropriate Fc receptors. Antibodies directed to the ot(3 heterodimer can behave similarly. Thus, a T cell bridged to an antigen-presenting cell via TCR/mAb/FcR reacts in a manner analogous to the physiological situation, where the link is TCR/Ag/MHC (major histocompatibility complex). For signaling through the TCR, therefore, some form of cross-linking or partial immobilization of the receptor is necessary, which need not be dependent on specific antigen recognition. This signaling process takes place through the invariant subunits of the TCR, since the heterodim-eric antigen-binding chains themselves have very small cytoplasmic domains which are unlikely to have more than an anchoring function. In peripheral T cells, full activation also requires signaling through the costimulatory CD28 molecule by the B7-1/B7-2 antigen on B cells and macrophages. Signaling through the TCR alone results in the functionally unresponsive state known as anergy.

T lymphocyte activation involves multiple intracellular events, all leading to transition from the quiescent G0 phase of the cell cycle into G, and induction of interleukin 2 (IL-2) secretion and IL-2 receptor expression. T cell growth, involving pro gression from G, to S phase and mitosis, is then controlled by IL-2 binding to the IL-2 receptor. At least two signaling pathways are thought to result from TCR occupancy, the first routing through the G protein p21ras, and the second through phospholipase C. Both pathways act synergistically with CD28-derived signals to effect action of the transcription factor NF-AT1 (nuclear factor of activated T cells) on, for example, the IL-2 gene.

During antigen recognition by the TCR on a CD4+ helper T cell, the coreceptor molecule CD4 is recruited into the receptor complex, having associated with monomorphic sites on the MHC class II molecule of the antigen-presenting cell. The Src family protein tyrosine kinase p56lck associates with CD4 and, in one model of the molecular consequences of antigen binding, p56lck phosphorylates the CD3 and £ chains on the tyrosine residues within their Reth activation domains. This promotes association of the TCR with the T cell-specific protein tyrosine kinase ZAP-70 through its SH2 domains, when ZAP-70 itself becomes phosphorylated and provides a signal to both p21riS and phospholipase C pathways via intermediate protein species.

The structure of the TCR thus reflects its two major functions of antigen recognition and signal transduction, with the latter role being governed by the invariant chains. The CD3 proteins, together with the £ chain, must interact with other cell surface molecules, including CD4 and CD8, and several intracellular proteins such as p56'ck and ZAP-70, as well as other tyrosine and serine/threonine kinases. It is now apparent that the complexity of the TCR is not unique, with other receptors governing cellular activation, such as the B cell antigen receptor (surface IgM), the Fc receptors and the IL-2 receptor, also having oligomeric structures commensurate with their complex function.

See also: CD4; CD8; CD28; CD45 (the leukocyte common antigen); Fc receptors; IgM; Interleukin 2; Interleukin 2 receptor; Protein kinases; T cell receptor, «p; T cell receptor, 78; T cell receptor, recognition by; T lymphocyte activation; T lymphocyte differentiation.

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