Accumulation of cAMP within the T cell cytosol induces the activity of protein kinase A (PKA) and of exchange protein directly activated by cAMP (EPAC). PKA, the dominant effector of the cAMP signaling pathway (164) is an heterotetramer comprising two catalytic (C) subunits, maintained in an inactive state by tethering to two regulatory (R) subunits (165). Binding of cAMP to the R-subunits induces a conformational change resulting in the release of the C-subunits (166). As a result, liberated PKA C-subunits within T cells phosphorylate a wide variety of substrates affecting multiple signaling pathways (167). It is well established that sustained PKA activity disrupts signaling induced by triggering of the TCR, of the co-stimulatory receptor CD28 (168, 169) as well as by the IL-2 receptor (IL-2R) (170). Negative regulators of these signaling pathways, whose activity is bolstered by PKA, include Csk (171), SHP-1 (172), SHIP1 (173), HPK1 (174), and PP2A (175). Conversely, PLCγ1 (176, 177), Raf-1 (178, 179), JAK3 (170), RhoA (180, 181), VASP (182) as well as the transcription factors NFAT (183, 184) and NFkB (185, 186) constitute mediators or endpoint effectors of the aforementioned axes whose activity is dampened by PKA.