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Perry et al.
2002
). In addition to interacting with a common site in the catalytic
domain of all PDE4Ds (Perry et al.
2002
),
b
-arrestins also interact specifically with
the N-terminus of PDE4D5, making this isoform a preferred binding partner for
b
-arrestin (Bolger et al.
2003
). Intriguingly, we found that TCR/CD28 costimulation
led to profound recruitment of
b
-arrestin to T-cell lipid raft fractions concurrently
with PDE4 and that
b
-arrestin and PDE4D preexist in a complex prior to stimulation,
indicating that they are recruited to rafts together (Abrahamsen et al.
2004
).
TCR-induced cAMP production in lipid rafts results in PKA activation and the
subsequent inhibition of proximal T-cell signaling. However, overexpression of
PDE4 isoforms or
b
-arrestin has been demonstrated to increase T-cell activation,
revealing regulatory roles for both proteins in T-cell signaling (Abrahamsen et al.
2004
). In conclusion, the activities of both PKA and PDE4, therefore, seem to be
important for the regulation of TCR-induced signaling and T-cell function.
We propose a novel role for TCR and CD28 costimulation in downmodulation
of TCR-induced cAMP-mediated inhibitory signals through the recruitment of a
PDE4/
b
-arrestin complex to lipid rafts, thus allowing a full T-cell response to
occur. Interestingly, the cAMP inhibitory pathway has been implicated in several
immune diseases. HIV-infected patients have T cells with elevated cAMP levels
and hyperactivated PKA, and targeting the cAMP-PKA-Csk inhibitory pathway by
selective antagonists reverses T-cell dysfunction in HIV cells
ex vivo
(Aandahl
et al.
1998
,
1999
). Improved
in vivo
T-cell function has been observed targeting
COX-2, thereby reducing PGE
2
production and reducing the cAMP levels
(Johansson et al.
2004
; Kvale et al.
2006
). Furthermore, a high proportion
of patients with common variable immunodeficiency (CVID) show T-cell abnorm-
alities. Recent findings demonstrating increased PKA activation and impaired
IL-10 secretion by T cells from these patients suggest a link between T-cell
deficiency and impaired B-cell function in CVID, indicating that the cAMP-PKA
pathway is a target for therapeutic immunomodulation in CVID (Aukrust et al.
1999
; Holm et al.
2003
).
1.3.2 PDE4/
-Arrestin Recruitment to T-Cell Lipid Rafts is Regulated
by Phosphatidylinositol 3-Kinase (PI3K)
b
Recruitment of
b
-arrestin and PDE4 to lipid rafts was not only observed upon TCR/
CD28 costimulation. CD28 stimulation alone seems to be enough to recruit these
proteins, whereas only very low levels comparable to basal levels were observed
Fig. 2 (continued) Increased cAMP levels lead to activation of PKA, phosphorylation and
activation of Csk, and inhibition of Lck, thus preventing full T-cell activation (a). However,
TCR/CD28 costimulation downmodulates the TCR-induced cAMP-mediated inhibitory signals
through recruitment of a PKB/
b
-arrestin/PDE4 complex leading to cAMP degradation, thus
allowing a full T-cell response to occur. Recruitment of this complex is dependent on phospha-
tidylinositol 3-kinase (PI3K) activity and PIP3 production, and the complex is targeted to the
membrane via the pleckstrin homology (PH) domain of PKB (b)
