Journal
NATURE IMMUNOLOGY
Volume 19, Issue 5, Pages 497-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-018-0083-5
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Funding
- Francis Crick Institute (Crick Core) from Cancer Research UK [FC001126, FC010110]
- UK Medical Research Council [FC001126, FC010110, MRC U117565642]
- Wellcome Trust [FC001126, FC010110, WT098326MA, 103760/Z/14/Z]
- European Research Council [695093, 294682-TB-PATH (Crick 10127)]
- UK Medical Research Council (MRC Centenary Award)
- UK Medical Research Council (MRC eMedLab Medical Bioinformatics Infrastructure Award) [MR/L016311/1]
- Crick Core projects [10101, FC001051]
- Agence Nationale de la Recherche [ANR-11-BSV3-0026]
- Fondation pour la Recherche Medicale [DEQ. 20110421320]
- Inserm/CNRS [ANR-11-BSV3-0026]
- Agence Nationale de la Recherche (ANR) [ANR-11-BSV3-0026] Funding Source: Agence Nationale de la Recherche (ANR)
- European Research Council (ERC) [695093] Funding Source: European Research Council (ERC)
- MRC [MC_U117565642] Funding Source: UKRI
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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(H)1 subset of helper T cells (malaria), T(H)2 cells (allergy) and T(H)17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in T(H)1 and T(H)2 responses, T(H)17 cell-mediated pathology was reduced in this context, with an accompanying decrease in T(H)17 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 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.
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