T Cell Receptor (TCR) Signaling

One of the first steps in the generation of the immune response is the recognition by T lymphocytes of peptide fragments (antigens) derived from foreign pathogens that are presented on the surface of antigen presenting cells (APC). This event is mediated by the T cell receptor (TCR), which transduces these extracellular signals by initiating a wide array of intracellular signaling pathways. One of the first biochemical events following TCR activation is the activation of Src family tyrosine kinases (p56^lck) that, in turn, phosphorylate phospholipase Cg₁ (PLCg₁). Activation of PLCg₁ leads to hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP₂), generating diacylglycerol (DAG) and inositol trisphosphate (IP₃). DAG activates protein kinase C (PKC) that, in turn, phosphorylates Ras, a GTPase that activates Raf leading to recruitment of the MAP kinase cascade. IP₃ releases calcium from its intracellular stores in the endoplasmic reticulum (ER). The Ca²⁺ binds to calmodulin that, in turn, activates calcineurin, a Ca²⁺/calmodulin dependent protein phosphatase. NFAT, a transcriptional regulator of interleukin-2 (IL-2) gene expression, is a direct target of calcineurin. Calcineurin dephosphorylates the cytosolic component of NFAT, NFATc, which migrates to the nucleus and induces transcription of the IL-2 gene.

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References:

Samelson, L.E., et al., Signal transduction mediated by the T-cell antigen receptor. Ann. NY Acad. Sci., 7, 157-172 (1995).

Hama, N., et al., Calcium/calmodulin-dependent protein kinase II down regulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. J. Exp. Med., 181, 1217-1222 (1995).

Germain, R.N., and Stefanova, I., The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol., 17, 467-522 (1999).