Review Cyclic AMP-mediated immune regulation — Overview of mechanisms of action in T cells Randi Mosenden, Kjetil Taskén ⁎ The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, P.O. Box 1125 Blindern, N-0317 Oslo, Norway abstract article info Article history: Received 28 June 2010 Received in revised form 23 November 2010 Accepted 25 November 2010 Available online 2 December 2010 Keywords: cAMP Immune regulation Protein kinase A Regulatory T cell T cell The canonical second messenger cAMP is well established as a potent negative regulator of T cell immune function. Through protein kinase A (PKA) it regulates T cell function at the level of transcription factors, members of the mitogen-activated protein kinase pathway, phospholipases (PLs), Ras homolog (Rho)A and proteins involved in the control of cell cycle progression. Type I PKA is the predominant PKA isoform in T cells. Furthermore, whereas type II PKA is located at the centrosome, type I PKA is anchored close to the T cell receptor (TCR) in lipid rafts by the Ezrin–ERM-binding phosphoprotein of 50 kDa (EBP50)-phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) scaffold complex. The most TCR-proximal target for type I PKA is C-terminal Src kinase (Csk), which upon activation by raft recruitment and phosphorylation inhibits the Src family tyrosine kinases Lck and Fyn and thus functions to maintain T cell homeostasis. Recently, induction of cAMP levels in responder T cells has emerged as one of the mechanisms by which regulatory T (T R ) cells execute their suppressive action. Thus, the cAMP-type I PKA–Csk pathway emerges as a putative target for therapeutic intervention in autoimmune disorders as well as in cancer, where T R cell-mediated suppression contributes to suboptimal local immune responses. © 2010 Elsevier Inc. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 2. Protein kinase A (PKA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 3. T cell activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011 4. Cyclic AMP-mediated immune regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011 4.1. Mechanisms for PKA-mediated modulation of T cell immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011 4.2. The cAMP-type I PKA-C-terminal Src kinase (Csk) pathway in T cell lipid rafts . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013 4.3. Induction of cAMP levels in responder T cells as a mechanism of T R cell action . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014 5. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015 Cellular Signalling 23 (2011) 1009–1016 Abbreviations: AC, Adenylyl cyclase; AKAP, A-kinase anchoring protein; AKAP-KL, AKAP-kidney lung; AKB, A-kinase binding domain; AP-1, Activator protein 1; ATF, Activation transcription factor; C, Catalytic (subunit of PKA); CBP, CREB-binding protein; CNG, Cyclic nucleotide-gated; CRE, cAMP response element; CREB, CRE-binding protein; CREM, CRE modulator; Csk, C-terminal Src kinase; D-AKAP, Dual-specificity AKAP; EBP50, ERM-binding phosphoprotein of 50 kDa; Epac, Exchange protein activated by cAMP; ERK, Extracellular signal-regulated kinase; ERM, Ezrin/Radixin/Moesin; FERM, N-terminal band 4.1 ERM; FOXP3, Forkhead box protein-3; Gα, G protein α; GPR83, G protein-coupled receptor 83; GPCR, G protein-coupled receptors; HePTP, Hematopoietic protein tyrosine phosphatase; ICER, Inducible cAMP early repressor; IKK, IκB kinase; ITAM, Immunoreceptor tyrosine- based activation motif; IκB, Inhibitor of κB; LAT, Linker for activation of T cells; mAKAP, Muscle AKAP; MHC, Major histocompatibility complex; MTG, Myeloid translocation gene; NFκB, Nuclear factor κB; NFAT, Nuclear factor of activated T cells; PAG, Phosphoprotein associated with glycosphingolipid-enriched micro-domains; PAP7, Peripheral benzodiazepine receptor-associated AKAP protein; PDE, Phosphodiesterase; PG, Prostaglandin; PKA, Protein kinase A; PL, Phospholipase; R, Regulatory (subunit of PKA); Rap, Ras-proximate; Rho, Ras homolog; RIAD, RI anchoring disruptor; RISR, RI specifier region; SHP, SH2 domain containing tyrosine phosphatase; STAT, Signal transducer and activator of transcription; TCR, T cell receptor; T R , Regulatory T (cell); UCR, Upstream conserved region; WAVE, Wiskott-Aldrich syndrome protein verprolin homologous protein; Zap-70, ζ-chain-associated protein of 70 kDa. ⁎ Corresponding author. The Biotechnology Centre, University of Oslo, P.O. Box 1125 Blindern, N-0317 Oslo, Norway. Tel.: +47 22840505; fax: +47 22840506. E-mail address: kjetil.tasken@biotek.uio.no (K. Taskén). 0898-6568/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2010.11.018 Contents lists available at ScienceDirect Cellular Signalling journal homepage: www.elsevier.com/locate/cellsig