ICOS-pathway in T-helper cell
Induction of an immune response requires that T cells receive 2 sets of signals from
antigen-presenting cells. First antigen-specific signal is delivered through T cell
receptor alpha/ beta (TCR alpha/beta) - CD3
complex, while the second co-stimulatory signal is provided by
co-receptors, such as CD28 molecule (CD28) and
Inducible T-cell co-stimulator (ICOS) .
ICOS acts as a costimulatory signal for
T-cell proliferation and cytokine secretion, and mediates local tissue responses to
inflammatory conditions, modulates secondary immune response by co-stimulating memory
T-cell function. ICOS stimulation plays an important role in
cell-cell signaling, cytoskeleton, immune responses, and regulation of cell survival.
Iinducible T-cell co-stimulator ligand (ICOS-L) is a ligand
for ICOS .
TCR alpha/beta/CD3 complex bound to Major
histocompatibility complex class II (MHC class II) initiates
a biochemical cascade via Lymphocyte-specific protein tyrosine kinase
(Lck) and Zeta-chain (TCR) associated protein kinase 70kDa
(ZAP70). Two known substrates of
ZAP70 are adapter molecules Linker for activation of T cells
(LAT) and Lymphocyte cytosolic protein 2
(Slp76). Phosphorylation of
tyrosine residues on LAT and Slp76
results in recruitment of a number of other proteins involved in
activation of different signaling cascades. The phosphorylated adaptor
LAT binds and activates Phospholipase C, gamma 1
(PCL-gamma 1) . The activated
PCL-gamma 1 is responsible for production of second
messengers diacylglycerol (DAG) and inositol 1, 4,
5-triphosphate (IP3) from cleavage of phospha-tidylinositol
4, 5 bisphosphate (PtdIns(4,5)P2) at plasma membrane.
IP3 and DAG are second
messengers that regulate various processes, such as activation of Nuclear factor of
activated T-cells, cytoplasmic, calcineurin-dependent 2
(NF-AT1(NFATC2)) and Nuclear factor of kappa light
polypeptide gene enhancer in B-cells
DAG activates Protein kinaseC-theta
PKC- theta activates Inhibitor
of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKK
beta), which phosphorylates Nuclear factor of kappa light polypeptide gene
enhancer in B-cells inhibitor (I-kB) thereby allowing
activation of NF-kB complex.
IP3 induces release of Ca('2+)
from endoplasmatic reticulum. Calcium-bound Calmodulin 2
(Calmodulin) associates with and activates Protein
phosphatase 3 (formerly 2B), catalytic subunits (Calcineurin A
(catalytic)). Calcineurin A (catalytic)
dephosphorylates NF-AT1(NFATC2) family of
transcription factors leading to theirs translocation into the nucleus .
CD28 is stimulated by binding of B-cell-specific
cell-surface receptors CD86 molecule
(CD86) and CD80 molecule
(CD80). CD28 enhances T-cell
functions that are essential for effective antigen-specific immune response . In response to activation by the ligands, CD28
can bind to the Phosphatidylinositol 3-kinase, regulatory subunit (PI3K reg
class IA), adaptor proteins Growth factor receptor-bound protein 2
(GRB2), and T cell-specific
IL2-inducible T-cell kinase (ITK).
ITK participates in phosphorylation of LAT
and in the activation of PCL-gamma 1 , .
Slp76 and GRB2 recruit Vav 1
guanine nucleotide exchange factor (VAV-1), which activates
small GTPases Ras-related C3 botulinum toxin substrate 1
(Rac1) and Cell division cycle 42
(CDC42) involved in regulation of cytoskeleton structure and
T-cell receptor itself can't bind and activate phosphatidylinositol kinase. This role
is played by T cell receptor associated transmembrane adaptor 1
(TRIM), which is a novel integral component of
TCR alpha/beta/CD3 complex co-stimulators .
Additionally, CD28 and ICOS
recruit and activate Phosphatidylinositol kinase.
and ICOS bind to PI3K reg class
IA and recruit it to the membrane thereby activating kinase activity.
Active Phosphatidylinositol 3-kinase, catalytical subunit PI3K cat class IA
converts phosphatidylinositol 4,5-biphosphate
(PtdIns(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate
(PtdIns(3,4,5)P3) . Another
phosphatidylinositol kinase isoform, Phosphoinositide-3-kinase, regulatory subunit 5
(PI3K reg class IB (p101)) - Phosphoinositide-3-kinase,
catalytic, gamma polypeptide (PI3K cat class IB
(p110-gamma)), is stimulated by the signal from GPCR via
G-protein beta/gamma. PtdIns(3,4,5)P3
is a second messenger and modulates the activity of v-akt murine thymoma
viral oncogene homolog (AKT(PKB)) and 3-phosphoinositide
dependent protein kinase-1 (PDK(PDPK1)) involved in cell
survival processes .
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