Cyclic AMP-mediated immune regulation--overview of mechanisms of action in T cells.
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.
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.
Randi
R
Mosenden
Kjetil
K
Taskén
D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000276:immunology* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D021962:Membrane Microdomains; D011487:Protein Conformation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D054758:A Kinase Anchor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000242:Cyclic AMP; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases