T Cell Receptor TCR Signaling

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T Cell Receptor (TCR) Signaling
SIGMA-ALDRICH
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T Cell Receptor (TCR) Signaling One of the first
steps in the generation of the immune response is
the recognition by T lymphocytes of peptide
fragments (antigens) derived from foreign
pathogens that are presented on the surface of
antigen presenting cells (APC). This event is
mediated by the T cell receptor (TCR), that
transduces these extracellular signals by
initiating a wide array of intracellular
signaling pathways. One of the first biochemical
events following TCR activation is the activation
of Src family tyrosine kinases (p56lck) that, in
turn, phosphorylate phospholipase C?1 (PLC ?1).
Activation of PLC ?1 leads to hydrolysis of
phosphatidylinositol 4, 5-bisphosphate (PIP2),
generating diacylglycerol (DAG) and inositol
trisphosphate (IP3). DAG activates protein kinase
C (PKC) that, in turn, phorphorylates Ras, a
GTPase that activates Raf leading to recruitment
of the MAP kinase cascade. IP3 releases calcium
from its intracellular stores in the endoplasmic
reticulum (ER). The Ca2 binds to calmodulin
that, in turn, activates calcineurin, a
Ca2/calmodulin dependent protein phosphatase.
NFAT, a transcriptional regulator of
interleukin-2 (IL-2) gene expression, is a direct
target of calcineurin. Calcineurin
dephosphorylates the cytosolic component of NFAT,
NFATc, which migrates to the nucleus and induces
transcription of the IL-2 gene. References Samelso
n, L.E., et al., Signal transduction mediated by
the T-cell antigen receptor. Ann. NY Acad. Sci.,
7, 157-172 (1995). Hama, N., et al.,
Calcium/calmodulin-dependent protein kinase II
down regulates both calcineurin and protein
kinase C-mediated pathways for cytokine gene
transcription in human T cells. J. Exp. Med.,
181, 1217-1222 (1995). Germain, R.N., and
Stefanova, I., The dynamics of T cell receptor
signaling complex orchestration and the key
roles of tempo and cooperation. Annu. Rev.
Immunol., 17, 467-522 (1999).