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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. |
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.