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-based 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. Zeta-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 Ca²⁺ from the ER, which promotes entry of extracellular Ca²⁺ into cells through calcium release-activated Ca²⁺ (CRAC) channels. Calcium-bound calmodulin (Ca²⁺/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:

• Burbach BJ, Medeiros RB, Mueller KL, Shimizu Y (2007) T-cell receptor signaling to integrins. Immunol. Rev. 218, 65–81.
• Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13(4), 227–42.
• Cheng J, Montecalvo A, Kane LP (2011) Regulation of NF-κB induction by TCR/CD28. Immunol. Res. 50(2-3), 113–7.
• Cronin SJ, Penninger JM (2007) From T-cell activation signals to signaling control of anti-cancer immunity. Immunol. Rev. 220, 151–68.
• Fracchia KM, Pai CY, Walsh CM (2013) Modulation of T Cell Metabolism and Function through Calcium Signaling. Front Immunol 4, 324.
• Marsland BJ, Kopf M (2008) T-cell fate and function: PKC-theta and beyond. Trends Immunol. 29(4), 179–85.
• Thome M (2008) Multifunctional roles for MALT1 in T-cell activation. Nat. Rev. Immunol. 8(7), 495–500.

We would like to thank Prof. Sankar Ghosh, Columbia University, New York, NY for contributing to this diagram.