b-Arrestins in the Immune System - Progress in Molecular Biology and Translational Science - page 356

suppression of apoptosis mediated by stimulated GPCRs, as demonstrated
using b -arrestin 1/2-knockout cells. 57 IGF1-mediated antiapoptosis was
diminished by knockdown of b -arrestin 1/2 and was restored by transfection
of b -arrestin 1. 56 b -Arrestin 1 epigenetically regulates Bcl2 expression, reg-

ulating the survival and homeostasis of CD4 þ T cells. 46

b -Arrestin 1 pro-
motes acetylation of histone H4 59 at the Bcl2 locus and Bcl2 expression
in both na ¨ ve and activated CD4 þ T cells. 46 Furthermore, b -arrestin 1 is
highly expressed in CD4 þ T cells frommultiple sclerosis patients, and RNAi
knockdown of b -arrestin 1 in those cells increased apoptosis after induction
by cytokine withdrawal. 46 b -Arrestin 1 did not affect the homeostasis of

CD8 þ T cells, 46 possibly due to the difference in the subcellular distribution
of b -arrestin 1 in CD4 þ and CD8 þ T cells. Moreover, b -arrestin 2 over-
expression and interference can decrease and increase, respectively, the level
of gp120/morphine-induced lymphocyte apoptosis. 60 Collectively, these
studies support a role for b -arrestins in regulating lymphocyte survival.

3.5. TH1, TH2, and TH17 cells
Classically, helper T cells include Th1 and Th2 T cells. T-cell antigen
receptor-mediated activation of the Ras/MAP kinase pathway controls
IL-4 receptor function and Th2 cell differentiation. 61 Although the direct
demonstration of a role for b -arrestins in Th1 and Th2 skewing is lacking,
it seems that b -arrestins play a role in both conditions. For example,
b -arrestin-2-deficient mice showed reduced CD4 þ T-cell accumulation
in the airway in an asthma model. 55 This may be a Th2-dependent event
as b -arrestin-2-deficient mice showed a normal inflammatory response in
an LPS model. 55 Knocking down b -arrestin 2 with RNAi decreased the
expression of the Th2 cytokine IL-4, as well as the T-cell-specific transcrip-
tion factor GATA3 in CD4 þ T lymphocytes after terbutaline stimulation. 47
On the other hand, overexpression of b -arrestin 1 increased production of
the Th1 cytokine, interferon- g . 59 The stress-induced suppression of Th1
cytokines and the increased production of Th2 cytokines were greatly
enhanced in b -arrestin 2-deficient mice compared with wild-type mice. 62
These studies suggest that b -arrestins may not have a role in T-cell differ-
entiation but have a role in Th1 and Th2 responses during inflammation.
The involvement of b -arrestins in Th17 cell function has not been
reported. Blocking CCL2-CCR2 interactions with a fusion peptide failed
to recruit b -arrestin 2, leading to blockade of IL-17 production in vitro. 63