T Cell Receptors

Signalling cascade stimulated by the TCR showing the key protein components.

Reprinted from Immunology 113, T. Razzaq, P. Ozegbe, E. Jury, P. Sembi, N. Blackwell and P. Kabouridis, Regulation of T-cell receptor signalling by membrane microdomains, PP.413-426, 2004, PMID: 15554919.

T Cell Receptor-induced Responses

The TCR is a transmembrane heterodimer composed of an a and a b chain, but is insufficient on its own to transduce a signal, in part due to their short cytoplasmic tails. TCRs are in close contact with CD3 (composed of subunits CDe(2)-CDg-CDd) and z (also called zeta, or CDz) transmembrane proteins, which together form the TCR complex (pictured above). The CD3 and z proteins are responsible for transmitting the signal into the cell via conserved motifs (immunoreceptor tyrosine-based activation motif, or ITAM) in their cytoplasmic domains, which act as tyrosine kinase substrates, and once phosphorylated, as binding sites for other kinases. The TCR complex is coupled to cytoplasmic tyrosine kinases (such as from the Src (Lck) and Syk (Zap-70) families), which act in conjunction with a myriad of adaptor proteins to initiate signals that bring about T cell activation.

However, antigen binding does not always mount an immune response; for instance as occurs with TCR binding to self-antigens which elicits immune tolerance. To mount an immunological response, the T cell needs to receive a second signal from an antigen-presenting cell in the form of a costimulatory molecule. Costimulatory molecules act through different T cell receptors, such as the CD28 and TNFR (tumour necrosis factor receptor) families, producing a second signal that induces T-cell activation and proliferation. The CD28 and TNFR costimulatory receptors possibly exert their effect through promoting more efficient signalling by concentrating the kinases and substrates that are required to initiate a signal. Many different costimulatory molecules have been identified, some of which can have a negative effect on signal initiation, such as B and T lymphocyte attenuator (BTLA).

Changes in the activity of T cell signalling pathways can lead to pathological conditions, such as autoimmunity (breaking of self-tolerance) and AIDS. HIV binds to CD4 molecules, enabling them to infect CD4+ T cells, resulting in the reduction of both infected and uninfected T cells.

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