T Cell Receptor Signaling
Pathway Description:
T Cell Receptor (TCR) activation promotes a number of signaling cascades that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation. An early event in TCR activation is phosphorylation of immunoreceptor tyrosine-base activation motifs (ITAMs) on the cytosolic side of the TCR/CD3 complex by lymphocyte protein-tyrosine kinase (LCK). The CD45 receptor tyrosine phosphatase modulates the phosphorylation and activation of Lck and other Src family tyrosine kinases. ζ-chain associated protein kinase (Zap-70) is recruited to the TCR/CD3 complex where it becomes activated, promoting recruitment and phosphorylation of downstream adaptor or scaffold proteins. Phosphorylation of SLP-76 by Zap-70 promotes recruitment of Vav (a guanine nucleotide exchange factor), the adaptor proteins NCK and GADS, and an inducible T cell kinase (ITK). Phosphorylation of phospholipase C γ1 (PLCγ1) by ITK results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messengers diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates PKCθ and the MAPK/Erk pathways, both promoting transcription factor NF-κB activation. IP3 triggers the release of Ca++ from the ER, which promotes the entry of extracellular Ca++ into cells through calcium release-activated Ca++ (CRAC) channels. Calcium-bound calmodulin (Ca++/CaM) activates the phosphatase calcineurin, which promotes IL-2 gene transcription through the transcription factor NFAT. Feedback regulation at several points within these pathways allows for different outcomes, depending on the cell type and environment. The incorporation of signals from additional cell surface receptors (such as CD28 or LFA-1) further regulates cellular response.
Selected Reviews:
- Germain RN, Stefanová I (1999) The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522.
- Isakov N, Altman A (2002) Protein kinase C(theta) in T cell activation. Annu. Rev. Immunol. 20, 761–94.
- Palacios EH, Weiss A (2004) Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 23(48), 7990–8000.
- Samelson LE, Donovan JA, Isakov N, Ota Y, Wange RL (1995) Signal transduction mediated by the T-cell antigen receptor. Ann. N. Y. Acad. Sci. 766, 157–72.
CST would like to thank Prof. Marc K. Jenkins and Daniel L. Mueller, M.D., University of Minnesota Medical School, Minneapolis, Minnesota, for creating this diagram.
created September 2004 • revised January 2007
