TCR Signaling

The T-Cell Receptor is a protein complex on the surface of T-cell responsible for antigen recognition. The activation induces a number of signaling cascades finally leading to the transcription of several gene products which allow the T cells to differentiate, proliferate and secrete a number of cytokines.

Src-family kinases (SFKs¹ ) Lck and Fyn phosphorylate TCR ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3, creating a docking site for ZAP-70. Phosphorylation and activation is modulated by CD45 receptor² . Zap-70 binds to CD3 zeta chain which positions the protein kinase to phosphorylate the transmembrane protein linker of activated T cells (LAT).

Signaling proteins like SLP-76 can now dock to LAT and gets phosporylated by ZAP-70 as well³. SLP-76 promotes recruitment of Vav (GEF), the adaptor proteins NCK and GADS, and an inducible T cell kinase (Itk). Ltk enables PLCγ1 by phosphorylation which leads to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messengers diacylglycerol (DAG) and inositol trisphosphate (IP3).

Phosphorylation of phospholipase C γ1 (PLCγ1) by Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messenger inositol trisphosphate (IP3) and DAG. DAG activates PKC⁴ and the MAPK/Erk pathways cascade which leads to activation of transcription factor NF-κB and ATF2 activation and relocation into nucleolus. IP3 promotes release of Ca2+ from the ER, which triggers entry of extracellular Ca2+ into cells through calcium release-activated Ca2+ (CRAC) channels. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase calcineurin. Transcription factor NFAT gets activated and promotes IL-2 gene transcription.

The signal cascades are regulated on several occasions to diversify the cell answer. Extracellular signals are recognized by additional cell surface receptors like CD28 or LFA-1 and further regulate cellular response.

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