c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4(+) T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we show that c-Maf regulates IL-10 production in CD4(+) T cells in T(H)1 (malaria), T(H)2 (allergy) and T(H)17 (autoimmunity) disease models in vivo. Although CD4-targeted Maf-deficient mice showed greater pathology in T(H)1 and T(H)2 responses, T(H)17-mediated pathology was reduced, with accompanying decreased T(H)17 and increased Foxp3(+) regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription factor network, including enhanced NFAT activity, leading to the identification and validation of c-Maf as a negative regulator of IL-2. Decreased Rorc resulting from c-Maf deficiency was dependent on IL-2, explaining the in vivo observations. Thus, c-Maf is a positive and negative regulator of cytokine gene expression, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.