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 TH1 (malaria), TH2 (allergy) and TH17 (autoimmunity) disease models in vivo. Although CD4-targeted Maf-deficient mice showed greater pathology in TH1 and TH2 responses, TH17-mediated pathology was reduced, with accompanying decreased TH17 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.

In the version of this article initially published, some of the references in Table 1 were incorrect. The correct references are as follows: in row 12, refs. 12,44 should be ref. 12; in row 16, refs. 2,17,27 should be ref. 109 (Walker, L. M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466-470 (2011)); in row 25, refs. 61,76 should be ref. 110 (Wu, X. et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856-861 (2010)); and in the bottom row, ref. 57 should be ref. 111 (Huang, J. et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406-412 (2012)). Those new references (109-111) should be included in the reference list.