The TCR for antigen and the CD4 or CD8 coreceptor together recognize complexes of peptide antigens and MHC molecules on APCs, and this recognition provides the initiating, or first, signal for T cell activation (Fig. 1). The TCRs expressed on all CD4+ and CD8+ T cells consist of an α chain and a β chain, both of which participate in antigen recognition. (A small subset of T cells expresses TCRs composed of γ and δ chains, which do not recognize MHC-associated peptide antigens.) The TCR of a T cell specific for a foreign (e.g., microbial) peptide recognizes the displayed peptide and simultaneously recognizes residues of the MHC molecule located around the peptide-binding cleft. Every mature MHC-restricted T cell expresses either CD4 or CD8, both of which are called coreceptors because they bind to the same MHC molecules that the TCR binds and are required for initiation of signaling from the TCR complex. At the time when the TCR is recognizing the peptide-MHC complex, CD4 or CD8 binds the class II or class I MHC molecule, respectively, at a site separate from the peptide-binding cleft.  when protein antigens are ingested by APCs from the extracellular milieu into vesicles, these antigens are processed into peptides that are displayed by class II MHC molecules. In contrast, protein antigens present in the cytosol are processed by proteasomes into peptides displayed by class I MHC molecules. Thus, because of the specificity of the coreceptors for different classes of MHC molecules, CD4+ and CD8+ T cells recognize peptides generated through different protein processing pathways. The TCR and its coreceptor need to be engaged simultaneously to initiate the T cell response, and multiple TCRs likely need to be triggered for T cell activation to occur. Once these conditions are achieved, the T cell begins its activation program.

Fig1. Antigen recognition and signal transduction during T cell activation. Different T cell molecules recognize antigen and deliver biochemical signals to the interior of the cell as a result of antigen recognition. The CD3 and ζ proteins are non-covalently attached to the T cell receptor (TCR) α and β chains by interactions between charged amino acids in the transmembrane domains of these proteins (not shown). The figure illustrates a CD4+ T cell; the same interactions are involved in the activation of CD8+ T cells, except that the coreceptor is CD8 and the TCR recognizes a peptide–class I MHC complex. APC, Antigen-presenting cell; ITAM, immunoreceptor tyrosine-based activation motifs; MHC, major histocompatibility complex.

The biochemical signals that lead to T cell activation are triggered by a set of proteins linked to the TCR that are part of the TCR complex and by the CD4 or CD8 coreceptor (see Fig. 1). In lymphocytes, antigen recognition and subsequent signaling are performed by different sets of molecules. The TCR αβ heterodimer recognizes antigens, but it is not able to transmit biochemical signals to the interior of the cell. The TCR is noncovalently associated with a complex of transmembrane signaling proteins including three CD3 proteins and a protein called the ζ chain. The TCR, CD3, and ζ chain make up the TCR complex. Although the α and β TCRs must vary among T cell clones in order to recognize diverse antigens, the signaling functions of TCRs are the same in all clones, and therefore the CD3 and ζ proteins are invariant among different T cells .

T cells can also be activated by molecules that bind to the TCRs of many or all clones of T cells, regardless of the peptide-MHC specificity of the TCR. For instance, some microbial toxins may bind to the TCRs of many T cell clones and also bind to MHC class II molecules on APCs without occupying the peptide-binding cleft. By activating a large number of T cells, these toxins induce excessive cytokine release and cause systemic inflammatory disease. They are called superantigens because, like conventional antigens, they bind to MHC molecules and to TCRs, but to many more than typical antigens do.