Biology Reference
In-Depth Information
occurring Tregs may degrade ATP and catalyze the generation of adenosine that acts
via the adenosine A2a receptor on activated effector T cells, thereby suppressing
their function by intracellular production of cAMP (Deaglio et al.
2007
). In
addition, continuous antigen exposure to T cells leads to generation of adaptive
Tregs (Aandahl et al.
2004
). Adaptive Tregs express cyclooxygenase 2 (COX-2),
leading to secretion of PGE
2
. PGE
2
stimulates FOXP3 expression in Tregs in
addition to inhibit effector T-cell function through activation of the cAMP-P-
KA-Csk signaling pathway (Mahic et al.
2006
). The different mechanisms affect-
ing effector T cells described above are schematically summarized in Fig.
1
.
The spatiotemporal regulation of cAMP levels within the cell is a result of the
combined action of ACs and phosphodiesterases (PDEs), which provide the only
mechanism for cAMP degradation (Conti and Jin
1999
; Houslay and Adams
2003
).
Specifically, compartmentalization of receptors, cyclases, and PKA by A-kinase-
anchoring proteins (AKAPs) (Michel and Scott
2002
) in addition to generation of
local pools of cAMP within the cell by the action of PDEs (Zaccolo and Pozzan
2002
) results in a high degree of specificity in PKA-mediated signaling, although
there are multiple receptors and targets all using cAMP as a second messenger.
PGE
2
[
cAMP
]
EP2/EP4
[
cAMP
]
COX-2
Continuous antigen
exposure
[
cAMP
]
FOXP3
A2a-receptor
Naive T cell
Effector T cell
Adaptive Treg
PGE
2
Adenosine
ATP/ADP
CD39/CD73
CD14/TLR4
LPS
Gap junction
FOXP3
Natural occuring
Treg
Monocyte
Fig. 1 Schematic model of cAMP-mediated induction of Treg cells and suppression of effector
T cells. Naturally occurring Tregs have high cAMP levels and mediate their suppressive function
by transferring cAMP to responder T cells through gap junctions. In addition, the ecto-enzymes
CD39 and CD73 expressed on naturally occurring Tregs degrade ATP/ADP and catalyze the
generation of adenosine, acting via the adenosine A2a receptor on activated effector T cells and
thereby suppressing their function by intracellular production of cAMP. Furthermore, continuous
activation of T cells results in generation of adaptive Tregs that express COX-2, leading to PGE
2
production. Increased PGE
2
levels stimulate further FOXP3 expression in Treg cells in addition to
inhibiting effector T-cell function. Finally, T-cell inhibiton and induction of FOXP3 due to PGE
2
secretion can also be a result of LPS-activated monocytes
