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T cell receptor signaling

Chaim M Roifman, MD, FRCPC, FCACB
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS


T cell recognition of antigen forms the basis of adaptive T cell immunity. Antigen is digested into peptides and bound to major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) for presentation to T cells. Recognition of self and foreign peptides by T cell receptor (TCR) complexes on immature thymocytes and mature T cells is necessary for the positive and negative selection of developing thymocytes and the functional responses of T cells. This topic briefly reviews signaling through the TCR complex, identifying the proteins involved and highlighting downstream targets of the signaling cascade.

TCR genetics, structure, and biology are covered in detail separately. (See "T cell receptor genetics" and "The adaptive cellular immune response", section on 'T cell activation' and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Overview of T cell receptor biology'.)

Reviews related to combined immunodeficiencies caused by defects in TCR complex molecules are also presented separately. (See "CD3/T cell receptor complex disorders causing immunodeficiency" and "Combined immunodeficiencies" and "ZAP-70 deficiency".)


TCR signaling in naïve T cells is initiated by TCR binding to peptide major histocompatibility complex (pMHC) complexes on the surface of antigen presenting cells (APCs). This engagement leads to a series of intracellular signaling events that culminate in the generation of a T cell response (figure 1) [1-3].

The Src-family protein tyrosine kinase Lck is first activated with resultant phosphorylation of CD3 coreceptor cytoplasmic domains, specifically at motifs known as immunoreceptor tyrosine-based activation motifs (ITAMs). These phosphorylated ITAMs on CD3-zeta serve as binding sites for the zeta chain-associated protein kinase, ZAP-70. ZAP-70 is activated by Lck-mediated phosphorylation and subsequent autophosphorylation. Activated ZAP-70 then phosphorylates a variety of linker/adapter proteins, such as linker for activation of T cells (LAT) and Src-homology 2 domain-containing 76-kDa leukocyte protein (SLP-76). Further signaling proteins are then recruited, resulting in calcium mobilization, actin cytoskeleton reorganization, and activation of Ras guanosine triphosphate hydrolases (GTPases).

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Literature review current through: Nov 2017. | This topic last updated: Feb 24, 2016.
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