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Nat Immunol. 2018 May;19(5):497-507. doi: 10.1038/s41590-018-0083-5. Epub 2018 Apr 16.

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

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The Francis Crick Institute, Laboratory of Immunoregulation and Infection, London, UK.
The Francis Crick Institute, Computational Biology Laboratory, London, UK.
The Francis Crick Institute, Malaria Laboratory, London, UK.
The Francis Crick Institute, Helminth Immunology Laboratory, London, UK.
The Francis Crick Institute, Advanced Sequencing Facility Laboratory, London, UK.
Heidelberg University, Institute of Pharmacology, Heidelberg, Germany.
Aix Marseille University, CNRS, INSERM, CIML, Marseille, France.
Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany.
The Francis Crick Institute, Developmental Dynamics Laboratory, London, UK.
UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK.
The Francis Crick Institute, Laboratory of Immunoregulation and Infection, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.


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.

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