Differential metabolic requirement governed by transcription factor c-Maf dictates innate γδT17 effector functionality in mice and humans

作者：Xu Chen, Yihua Cai, Xiaoling Hu, Chuanlin Ding, Liqing He, Xiang Zhang, Fuxiang Chen, Jun Yan · 发表于：Science Advances · 年份：2022 · DOI：10.1126/sciadv.abm9120 · 被引用次数：22 · 研究领域：Immune Cell Function and Interaction、T-cell and B-cell Immunology、Diabetes and associated disorders

Cellular metabolism has been proposed to govern distinct γδ T cell effector functions, but the underlying molecular mechanisms remain unclear. We show that interleukin-17 (IL-17)-producing γδ T (γδT17) and interferon-γ (IFN-γ)-producing γδ T (γδT1) cells have differential metabolic requirements and that the rate-limiting enzyme isocitrate dehydrogenase 2 (IDH2) acts as a metabolic checkpoint for their effector functions. Intriguingly, the transcription factor c-Maf regulates γδT17 effector function through direct regulation of IDH2 promoter activity. Moreover, mTORC2 affects the expression of c-Maf and IDH2 and subsequent IL-17 production in γδ T cells. Deletion of c-Maf in γδ T cells reduces metastatic lung cancer development, suggesting c-Maf as a potential target for cancer immune therapy. We show that c-Maf also controls IL-17 production in human γδ T cells from peripheral blood and in oral cancers. These results demonstrate a critical role of the transcription factor c-Maf in regulating γδT17 effector function through IDH2-mediated metabolic reprogramming.