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

Item Type:Article
Title:c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells
Creators Name:Gabryšová, L., Alvarez-Martinez, M., Luisier, R., Cox, L.S., Sodenkamp, J., Hosking, C., Pérez-Mazliah, D., Whicher, C., Kannan, Y., Potempa, K., Wu, X., Bhaw, L., Wende, H., Sieweke, M.H., Elgar, G., Wilson, M., Briscoe, J., Metzis, V., Langhorne, J., Luscombe, N.M. and O'Garra, A.
Abstract: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?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.
Keywords:CD4-Positive T-Lymphocytes, Gene Regulatory Networks, Interleukin-2, Proto-Oncogene Proteins c-maf, Animals, Mice
Source:Nature Immunology
Publisher:Nature Publishing Group
Page Range:497-507
Date:May 2018
Additional Information:Erratum in: Nat Immunol 20: 374.
Official Publication:https://doi.org/10.1038/s41590-018-0083-5
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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