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 found that c-Maf regulated IL-10 production in CD4⁺ T cells in disease models involving the T_H1 subset of helper T cells (malaria), T_H2 cells (allergy) and T_H17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in T_H1 and T_H2 responses, T_H17 cell–mediated pathology was reduced in this context, with an accompanying decrease in T_H17 cells and increase in Foxp3⁺ 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 RORγt (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.