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.
References:
- Braiman, A and Isakov, N (2015): "The Role of Crk Adaptor Proteins in T-Cell Adhesion and Migration”. Front. Immunol., v.6,2015. [PMID: 4593252]
- Courtney, AH (2017): “A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45. ”. Mol Cell , 3;67(3):498-511 [PMID: 28735895]
- Wang HY (2001): “Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.” J Biol Chem, 276(28):26004-11. [PMID: 11353765]
- Lio Y (1999): “Protein kinase C activation inhibits tyrosine phosphorylation of Cbl and its recruitment of Src homology 2 domain-containing proteins.” J Immunol, 162(12):7095-101 [PMID: 10358153]