A Winged Helix Forkhead (FOXD2) Tunes Sensitivity to cAMP in T Lymphocytes through Regulation of cAMP-dependent Protein Kinase RIα

Forkhead/winged helix (FOX) transcription factors are essential for control of the cell cycle and metabolism. Here, we show that spleens from Mf2−/− (FOXD2−/−) mice have reduced mRNA (507) and protein (357) levels of the RIα subunit of the cAMP-dependent protein kinase. In T cells from Mf2−/− mice, reduced levels of RIα translates functionally into ∼2-fold less sensitivity to cAMP-mediated inhibition of proliferation triggered through the T cell receptor-CD3 complex. In Jurkat T cells, FOXD2 overexpression increased the endogenous levels of RIα through induction of the RIα1b promoter. FOXD2 overexpression also increased the sensitivity of the promoter to cAMP. Finally, co-expression experiments demonstrated that protein kinase Bα/Akt1 work together with FOXD2 to induce the RIα1b promoter (10-fold) and increase endogenous RIα protein levels further. Taken together, our data indicate that FOXD2 is a physiological regulator of the RIα1b promoter in vivo working synergistically with protein kinase B to induce cAMP-dependent protein kinase RIα expression, which increases cAMP sensitivity and sets the threshold for cAMP-mediated negative modulation of T cell activation.