The T-cell receptor signalling pathway is an intracellular pathway that depicts how T-cells are activated as part of the cell-mediated immune response. T-cells are a type of lymphocyte produced by the thymus gland (T stands for thymus) that have a unique protein on their surface called the T-cell receptor. The T-cell receptor (TCR) is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules (PMID: 6336315). T-cells are activated when they encounter another immune cell such as a dendritic cell or a B-cell that has digested a protein antigen and displayed the resulting peptide antigen fragments on their surface MHC molecules. These antigen-bound dendritic or B-cells are called antigen-presenting cells or APCs. The MHC-antigen complex from these APCs binds to the TCR of a given T-cell and then, through a series of signalling events (depicted in this pathway), the T-cell begins to secrete cytokines (PMID: 19132916). Some cytokines help the T-cell mature while other cytokines spur the growth of even more T-cells. The MHC-antigen-TCR binding event activates several signalling pathways such as the PI3K pathway that generates inositol triphosphate (IP3) at the plasma membrane. This leads to the recruitment of signalling molecules like PDK1 (pyruvate dehydrogenase kinase 1), PLC-gamma-1 (phospholipase C-gamma), diacylglycerol (DAG) and others that are essential for the activation of PKC-theta (protein kinase C-theta), and eventually the production of interleukin-2 (IL-2) as well as other cytokines (PMID: 19132916). As shown in this pathway the antigen is first presented to the T-cell receptor (consisting of an alpha and beta subunit) and the CD3 glycoprotein complex (PMID: 19132916). An early event in TCR activation is the phosphorylation of certain tyrosine containing motifs on the cytosolic side of the TCR/CD3 complex by a protein known as lymphocyte protein tyrosine kinase or Lck. After this phosphorylation event, a protein called the zeta-chain associated protein kinase (Zap-70) is recruited to the phosphorylated TCR/CD3 complex where it becomes activated (PMID: 7539035). This promotes the recruitment and phosphorylation of other proteins. For instance, the phosphorylation of SLP-76 by Zap-70 promotes the recruitment of a protein known as Vav (a guanine nucleotide exchange factor), as well as the adaptor proteins NCK and GADS, and an inducible T cell kinase known as Itk. Phosphorylation of PLC-gamma-1 by Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the secondary messengers known as diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates PKC-theta and the MAPK/Erk pathways, both promoting transcription factor NF-kappa-B activation. IP3 triggers the release of calcium from the endoplasmic reticulum, which promotes entry of extracellular Ca2+ into the T-cells where it is bound by calmodulin. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase known as calcineurin (PMID: 22100452), which promotes IL-2 gene transcription through the transcription factor NFAT (Nuclear factor of activated T-cells) (PMID: 3260404).

T Cell Receptor Signaling Pathway References