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T Cell Receptor (TCR) Signaling
SIGMA-ALDRICH
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), that 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 (p56lck) that, in turn, phosphorylate
phospholipase C1 (PLC 1). Activation of PLC 1 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, phorphorylates Ras, a GTPase that
activates Raf leading to recruitment of the MAP kinase cascade. IP 3 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.
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, 467522 (1999).