Biology Reference
In-Depth Information
3.2. T-cell activation
T lymphocytes are activated by the binding of the T-cell receptor (TCR) to
antigens bound by major histocompatibility complex molecules on antigen-
presenting cells. The binding of costimulatory molecules to the CD28
receptor is also required for full T-cell activation. In addition, the activation
is mediated by kinases, phosphatases, and transcription factors. Engagement
of the TCR is followed by rapid cyclic AMP (cAMP) production in lipid rafts
and activation of the cAMP-protein kinase A (PKA)-Csk pathway inhibiting
proximal T-cell signaling.
48,49
It appears that
b
-arrestins do not regulate the
cAMP-PKA-Csk pathway.
48,49
However,
b
-arrestins participate in CD28
receptor coligation signaling.
49
Upon TCR and CD28 coligation,
b
-arrestin
was recruited to lipid rafts and augmented TCR/CD28-stimulated cytokine
production.
48,50
b
-Arrestins form complexes with cAMP phosphodiesterase
4 and mediate cross talk between phosphatidylinositol 3-kinase and cAM-
P-PKA signaling pathways.
51
A PDE4/
b
-arrestin complex attenuates
PKA phosphorylation of Csk,
48,52
allowing full T-cell activation to proceed.
3.3. Migration and chemotaxis
The migration of T cells is important in adaptive immune responses. T cells
must migrate to sites where antigen is found, because T cells respond to
pathogens only on direct contact with pathogen-derived antigen.
53
b
-Arrestins function as fundamental adaptors connecting receptors to cell
trafficking machinery.
48
b
-Arrestin-2-mediated activation of the p38
MAPK cascade is required for CXCR4-mediated migration of human
embryonic kidney 293 cells to CXCL12 (SDF-1
a
54
). It has been reported
that lymphocytes devoid of
b
-arrestin-2 demonstrate impaired migration
toward the chemotactic factor CXCL12
in vitro
.
45
A subsequent study
showed that
b
-arrestin-2-deficient mice have defective macrophage-
derived chemokine-mediated CD4
รพ
T-cell migration to the lungs,
55
and
T cells in
b
-arrestin-2-deficient mice exhibit migration defects in a model
of metastatic tumor growth.
17
3.4. Lymphocyte survival and apoptosis
Several studies indicate that
b
-arrestins play a critical role in preventing apo-
ptosis.
56,57
For example, neuropeptide substance P inhibits apoptosis via a
b
-arrestin scaffolding complex,
58
and
b
-arrestins play a critical role in the
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