A time-gated PKA-CREB signaling circuit licenses IL-12 responsiveness and Th1 fate in CD4+ T cells

Naive CD4 T cells can differentiate into Th1 cells after TCR stimulation with polarization of IL12 signaling. 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase, or protein kinase A (PKA), is a prototype for the large family of protein kinases that are crucial for signal transduction in eukaryotic cells. However, how PKA is involved in the process of Th1 differentiation is unknown. Here, we found that prolonged TCR signaling-mediated PKA activation was indispensable for Th1 differentiation. Rag1KO mice transferred with PKA-deficient naive CD4 T cells did not develop Th1-mediated colitis but showed robust inflammation with asthma signatures in the lungs, which was mediated by Th2 cells. Deficiency of PKA blocked both in vitro and in vivo Th1 differentiation of naive CD4 T cells. Mechanistically, loss of PKA in CD4 T cells resulted in a significant decrease in IL12RB2 expression induced by prolonged TCR signaling-mediated PKA activation. Moreover, in the late stage of TCR signaling stimulation, Ramp3 and Adm in activated T cells induced PKA activation, which led to IL12RB2 expression. Altogether, this study identifies a novel pathway involving PKA in regulating Th1 cell differentiation.