T cells bearing clonotypic T-cell receptors (TCRs) are generated from a pool of naïve progenitor cells by a two-stage process of positive and negative selection. The TCRs on these cells must recognize self peptides bound to self, or syngeneic, major histocompatibility complexes (MHCs) before they can differentiate from "double positives" into CD4+- or CD8+-expressing "single positives." However, positively selected T cells that are reactive against self-pMHCs are destroyed by negative selection. Positive selection establishes two subclasses of TCRs that associate with either of the two coreceptors CD8 (Fig. 1), and CD4:CD8+ T cells recognize pMHC class I molecules, while CD4+ T cells are activated by peptides bound to MHC class II.
ap TCRs are heterodimeric cell-surface glycoproteins that consist of disulfide-linked a and p chains and have a domain organization similar to antibodies (Fig. 2). Each chain is composed of an immunoglobulin (Ig)-like variable (V) and constant (C) domain, a transmembrane region, and a short cytoplasmic tail. The C domains serve to anchor the TCR in the membrane of the T cell and to interact with accessory signaling molecules such as CD3. The variable domains carry the complementarity-determining regions (CDRs), with which the TCR binds pMHC antigen with a generally low affinity, but moderate specificity.
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