Figure 2: Inhibitory pathway of prostaglandin E2 (PGE2) (adopted from Lone and Tasken [39]). (A) PGE2 mediatesTreg inhibition of effector Tcell (Tcon) function through a cAMP and PKA-mediated pathway. (A) In response to continuous antigen exposure, for instance in cancer and HIV, adaptiveTreg cells express cyclooxygenase-2 (COX-2) and PGE2, stimulates FOXP3 expression in these cells. TheTreg cell-derived PGE2 can signal through EP2 and EP4 receptors on Tcons to inhibit the function of these cells through pathway shown in (B). 21 Binding of PGE2 to its receptors on Tcons stimulates adenylyl cyclase activity, which increases intracellular cAMP levels and thus activates PKA. Aided by an Ezrin-EBP50-PAG scaffold, PKA phosphorylates Csk, which in turn phosphorylates Lck to inhibit its activity. Lck normally acts to promote TCR signaling; thus Lck inhibition through this PGE2- initiated pathway inhibits TCR signaling in Tcons.