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

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4.sup.+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4.sup.+ T cells in disease models involving the T.sub.H1 subset of helper T cells (malaria), T.sub.H2 cells (allergy) and T.sub.H17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in T.sub.H1 and T.sub.H2 responses, T.sub.H17 cell-mediated pathology was reduced in this context, with an accompanying decrease in T.sub.H17 cells and increase in Foxp3.sup.+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor ROR[gamma]t (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.