T cell receptor signaling pathway
T cell receptors (TCR) play a key role in functioning of
T cells and formation of the immunological synapse. It provides connection between T cell
and the antigen-presenting cell (APC) . TCRs are composed of
ligand-binding subunits, the alpha and beta chains, and signaling subunits, namely the
CD3 epsilon, gamma, delta and zeta chains. Small population of T cells contains TCRs that
consist of gamma and delta chains instead alpha and beta .
The coordinated activation of T cells by foreign antigens leads to a clonal expansion,
differentiation, cytotoxic killing, or induction of programmed cell death. The T-cell
activation is initiated by the TCR.
The physiologic ligand for the TCR alpha/beta is a
foreign peptide bound to the Major histocompatibility complex, class II
(MHC class II) expressed on the APC .
CD4 acts as a cellular adhesion molecule, binds
MHC class II molecules, and stabilizes the interaction of T
cells and APCs .
TCR alpha/beta ligation leads to the activation of the
Src family kinases Lck and Fyn.
How exactly these Src kinases are activated is not clear. However, it was shown that
tyrosine phosphatase CD45 participates in the formation of
multimeric complexes with the CD4 receptor that is
physically associated with Lck .
Additionally, CD45 dephosphorylates and activates
Lck and Fyn .
Activated Lck and Fyn
phosphorylate CD3 chains, and promote the recruitment and
subsequent activation of another tyrosine kinase ZAP-70
ZAP-70 phosphorylates adaptor LAT
that in turn binds to Phospholipase C gamma 1 (PCL-gamma
1) and activates it. Activated PCL-gamma 1 is
responsible for the production of the second messengers Diacylglycerol
(DAG) and Inositol 1,4,5-triphosphate
(IP3) by cleaving Phosphatidylinositol 4,5 bisphosphate
(PtdIns(4,5) P2) in the plasma membrane.
DAG activates a number of proteins, including various
isoforms of protein kinase C (PKC). Some of them
(PKC-theta in particular) participate in the Nuclear factor
NF-kappa-B (NF-kB) pathway .
Another second messenger, IP3, stimulates efflux of
Ca2+ from endoplasmic reticulum to the cytosol . Elevated Ca2+ levels activate the protein
Calcineurin dephosphorylates Nuclear factors of activated
T-cells NF-AT1(NFATC2), NF-AT2(NFATC1), NF-AT3(NFATC4), and
NF-AT4(NFATC3), which allow them to enter the nucleus where they
cooperates with other transcription factors and bind to promoter regions of specific
Ca2+ and DAG also activate
Calcium and diacylglycerol-regulated guanine nucleotide exchange factor II
(CalDAG-GEFII) that stimulates
H-Ras . Moreover, phosphorylated
LAT binds GRB2. The latter
activates Son of sevenless homolog 1 and 2 (SOS)/ v-Ha-Ras
Harvey rat sarcoma viral oncogene homolog (H-Ras)/ v-Raf-1
murine leukemia viral oncogene homolog 1 (c-Raf-1)/
Mitogen-activated protein kinase kinase 1 and 2
(MEK1 and MEK2)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2)
signaling. ERK1/2 kinases phosphorylate transcription factor
ELK1 member of ETS oncogene family (Elk-1) and transcription
factors of the Activator protein 1 (AP-1) family, such as
c-Fos. Thus, transcription factors AP-1, NF-kB and NFAT
participate in the immune response of the organism .
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