Histone Deacetylase SIRT1 Negatively Regulates the Differentiation of Interleukin-9-Producing CD4+ T Cells

Distinct metabolic programs support the differentiation of CD4+ T cells into separate functional subsets. In this study, we investigated metabolic mechanisms underlying the differentiation of IL-9-producing CD4+ T cells (Th9) in allergic airway inflammation and cancerous tumors. We found that histone deacetylase SIRT1 negatively regulated Th9 cell differentiation. A deficiency of SIRT1 induced by either conditional deletion in mouse CD4+ T cells or the use of small interfering RNA (siRNA) in mouse or human T cells increased IL-9 production, whereas ectopic SIRT1 expression inhibited it. Notably, SIRT1 inhibited Th9 cell differentiation that regulated anti-tumor immunity and allergic pulmonary inflammation. Glycolytic activation through the mTOR-hypoxia-inducible factor-1α (HIF1α) was required for the differentiation of Th9 cells that conferred protection against tumors and is involved in allergic airway inflammation. Our results define the essential features of SIRT1-mTOR-HIF1α signaling-coupled glycolytic pathway in inducing Th9 cell differentiation, with implications for metabolic reprogramming as an immunotherapeutic approach. [Display omitted] •Deficiency of SIRT1 in CD4+ T cells increased IL-9 production and glycolysis•Ectopic SIRT1 expression in CD4+ T cells inhibited IL-9 production and glycolysis•SIRT1-dependent Th9 cells regulated tumor and allergic pulmonary inflammation•TAK1-SIRT1-mTOR-HIF1α-glycolysis pathway was required for Th9 cell differentiation Th9 cells are critical in controlling immune-associated diseases. Liu and colleagues demonstrate that histone deacetylase SIRT1 negatively regulates the activities of mTOR and HIF1α signaling, couples with glycolysis metabolism, suppresses IL-9 production of CD4+ T cells, alleviates allergic airway inflammation, and promotes cancerous tumor growth.