Phosphodiesterases as Targets for Modulating T-Cell Responses - Phosphodiesterases as Drug Targets - page 346

diseases, and neurological disorders. PDEs are also interesting drug targets in
immunosuppression following transplantation and for modulation of immune
responses.

Keywords cAMP CD28 TCR T-cell function

1 Regulation of cAMP Levels in T Cells

The common and versatile second messenger cAMP controls numerous cellular
processes and is known to be a potent inhibitor of T-cell proliferation and cytokine
production (Aandahl et al. 2002 ; Skalhegg et al. 1992 ). Cyclic AMP can activate
protein kinase A (PKA) (Walsh et al. 1968 ), Epac (exchange protein directly
activated by cAMP) (de Rooij et al. 1998 ; Kawasaki et al. 1998 ), and cAMP-
regulated ion channels (Kaupp and Seifert 2002 ; Matulef and Zagotta 2003 ).
However, effects mediated by cAMP in T cells are most likely a result of PKA
activation as Epac and cAMP-gated channels are absent from or appear to be
expressed at low levels in T lymphocytes (our unpublished data and Kawasaki
et al. 1998 ). The cAMP-PKA signaling pathway in T cells is initiated by binding of
prostaglandin E 2 (PGE 2 ) and other extracellular ligands such as catecholamines,
serotonin, adenosine, and histamine to G protein-coupled receptors (GPCRs),
activation of adenylyl cyclase (AC), and the subsequent generation of cAMP
from ATP (Hanoune and Defer 2001 ). Endogenous cAMP levels in T cells are
also influenced by other mechanisms such as those described in the following
section involving regulatory T cells (Tregs).
Human Treg cells comprise 5-10% of the peripheral CD4 + T-cell population
(Ng et al. 2001 ) and are functionally characterized by their ability to suppress
effector T cells in addition to having an essential role in maintaining immunological
tolerance (Sakaguchi et al. 2001 , 2006 ; Sakaguchi 2004 ). This subset of CD4 + T
cells has been under intense research in the last decade due to its role in various
clinical conditions such as autoimmune disease, cancer, and chronic viral infections
(Beyer and Schultze 2006 ; Rouse et al. 2006 ; Sakaguchi et al. 2001 ). Tregs can
further be subdivided into naturally occurring Tregs that are derived in the thymus
and adaptive or peripherally induced Tregs that are developed from na ¨ ve T cells in
the periphery during immune activation (Bluestone and Abbas 2003 ). The role of
cAMP in induction of Tregs and Treg-mediated suppression is getting increasing
attention (reviewed in Yaqub and Tasken 2008 ). Naturally occurring Tregs have
been shown to have high cAMP levels and to mediate their suppressive function
by transferring cAMP to effector T cells through gap junctions (Bopp et al. 2007 ).
The high cAMP levels in Tregs can at least partly be explained by the FOXP3-
dependent downregulation of phosphodiesterase 3B (PDE3B) (Gavin et al. 2007 ).
Recently, it was also demonstrated that stimulation of mouse Tregs by IL-2 strongly
induced adenylyl cyclase 7 (AC7) activity, resulting in cAMP accumulation (Bazhin
et al. 2010 ). Furthermore, the ecto-enzymes CD39 and CD73 expressed on naturally