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

Journal Article: Nature ImmunologyYear Published: (2018) Volume Number: 19, Article Number: 497-507


Gabryšová,Leona; Alvarez-Martinez,Marisol; Luisier,Raphaëlle; Cox,Luke S; Sodenkamp,Jan; Hosking,Caroline; Pérez-Mazliah,Damián; Whicher,Charlotte; Kannan,Yashaswini; Potempa,Krzysztof; Wu,Xuemei; Bhaw,Leena; Wende,Hagen; Sieweke,Michael H; Elgar,Greg; Wilson,Mark; Briscoe,James; Metzis,Vicki; Langhorne,Jean; Luscombe,Nicholas M; O’Garra,Anne

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 TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell–mediated pathology was reduced in this context, with an accompanying decrease in TH17 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.