Gabryšová, L., Alvarez-Martinez, M., Luisier, R. et al.
Nature Immunology
倫敦帝國理工學院國家心肺研究所
CD4+ T helper (TH) lymphocytes are essential regulators of immune responses and inflammatory diseases. After being activated by professional antigen-presenting cells (APCs), TH cells differentiate into effector cells specialized in cytokine secretion and function. Effector TH cells have been classified as type 1 (TH1), type 2 (TH2), TH17 and Treg based on their cytokine expression profiles and immune regulatory function. Subsets of CD4+ helper T cells, including TH1, TH2 and TH17 cells, are critical for the eradication of specific pathogens, but if they are uncontrolled, they can contribute to immunopathology, either during infection or during immune system–mediated diseases. There are different mechanisms that keep the homeostasis of immune system including production of the anti-inflammatory cytokine IL-10 and CD4+ regulatory T cells (Treg cells). Many TFs have been shown to modulate Il10 expression, including c-Maf and although c-Maf has been shown to positively regulate Il10 expression in vitro, its effects on Il10 and global gene expression across different immune responses in vivo are unknown. In this paper, the author investigated the regulatory role of c-Maf in CD4+ T cells in vivo. Firstly, they checked the expression of Maf and that of Il10 correlate in all helper T cell and Treg cell subsets. Results showed that c-Maf might function as a common regulator of IL-10 in CD4+ T cells regardless of the T cell subset. Then they detected the role of c-Maf in different disease model and demonstrated that c-Maf deficiency in CD4+ T cells affects susceptibility to disease in a context-specific manner. To better understand the disease-specific effects of the deletion of Maf, they performed RNA-seq analysis of purified CD4+ T cells isolated from different organs in different disease models. Results showed that in addition to controlling TH1 and TH2 responses, c-Maf served a previously unknown, more dominant role in the EAE model, beyond IL-10 expression, by regulating the balance of TH17 cell responses (Rorc) and Foxp3+Treg cell responses. To identify the molecular mechanisms whereby c-Maf affects gene regulation in CD4+ T cells in vivo, the author used the assay for ATAC-seq to reveal functionally active genomic regions. Futher study showed that IL-2 is a c-Maf target. The decreased expression of Rorc observed in Maf-deficient TH17 cells was caused indirectly via the action of IL-2, since this effect was abolished by neutralization of IL-2. This paper demonstrated a broad and contextspecific role for c-Maf in regulating gene expression that allows each type of T cell effector immune response to occur in a controlled yet effective manner and suggested new potential drug target for different disease.