%A Wehbi,Vanessa L.
%A Taskén,Kjetil
%D 2016
%J Frontiers in Immunology
%C
%F
%G English
%K cAMP,AKAP,protein-protein interaction,T cell,prostaglandin
%Q
%R 10.3389/fimmu.2016.00222
%W
%L
%M
%P
%7
%8 2016-June-08
%9 Review
%+ Prof Kjetil Taskén,Nordic EMBL Partnership, Centre for Molecular Medicine Norway, Oslo University Hospital, University of Oslo,Norway,kjetil.tasken@medisin.uio.no
%+ Prof Kjetil Taskén,Jebsen Inflammation Research Centre, Oslo University Hospital,Norway,kjetil.tasken@medisin.uio.no
%+ Prof Kjetil Taskén,Biotechnology Centre, Oslo University Hospital, University of Oslo,Norway,kjetil.tasken@medisin.uio.no
%+ Prof Kjetil Taskén,Jebsen Centre for Cancer Immunotherapy, Oslo University Hospital,Norway,kjetil.tasken@medisin.uio.no
%+ Prof Kjetil Taskén,Department of Infectious Diseases, Oslo University Hospital,Norway,kjetil.tasken@medisin.uio.no
%#
%! AKAPs as regulator of cAMP-dependent immunomodulation in T cells
%*
%<
%T Molecular Mechanisms for cAMP-Mediated Immunoregulation in T cells – Role of Anchored Protein Kinase A Signaling Units
%U https://www.frontiersin.org/articles/10.3389/fimmu.2016.00222
%V 7
%0 JOURNAL ARTICLE
%@ 1664-3224
%X The cyclic AMP/protein kinase A (cAMP/PKA) pathway is one of the most common and versatile signal pathways in eukaryotic cells. A-kinase anchoring proteins (AKAPs) target PKA to specific substrates and distinct subcellular compartments providing spatial and temporal specificity for mediation of biological effects channeled through the cAMP/PKA pathway. In the immune system, cAMP is a potent negative regulator of T cell receptor-mediated activation of effector T cells (Teff) acting through a proximal PKA/Csk/Lck pathway anchored via a scaffold consisting of the AKAP Ezrin holding PKA, the linker protein EBP50, and the anchoring protein phosphoprotein associated with glycosphingolipid-enriched microdomains holding Csk. As PKA activates Csk and Csk inhibits Lck, this pathway in response to cAMP shuts down proximal T cell activation. This immunomodulating pathway in Teff mediates clinically important responses to regulatory T cell (Treg) suppression and inflammatory mediators, such as prostaglandins (PGs), adrenergic stimuli, adenosine, and a number of other ligands. A major inducer of T cell cAMP levels is PG E2 (PGE2) acting through EP2 and EP4 prostanoid receptors. PGE2 plays a crucial role in the normal physiological control of immune homeostasis as well as in inflammation and cancer immune evasion. Peripherally induced Tregs express cyclooxygenase-2, secrete PGE2, and elicit the immunosuppressive cAMP pathway in Teff as one tumor immune evasion mechanism. Moreover, a cAMP increase can also be induced by indirect mechanisms, such as intercellular transfer between T cells. Indeed, Treg, known to have elevated levels of intracellular cAMP, may mediate their suppressive function by transferring cAMP to Teff through gap junctions, which we speculate could also be regulated by PKA/AKAP complexes. In this review, we present an updated overview on the influence of cAMP-mediated immunoregulatory mechanisms acting through localized cAMP signaling and the therapeutical increasing prospects of AKAPs disruptors in T-cell immune function.