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.
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