T helper 9(Th9)cells are interleukin 9(IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation.Th9 cells differentiate from naïve CD4+T cells in the pres...T helper 9(Th9)cells are interleukin 9(IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation.Th9 cells differentiate from naïve CD4+T cells in the presence of IL-4 and transforming growth factor-beta(TGF-β);however,our understanding of the molecular basis of their differentiation remains incomplete.Previously,we reported that the differentiation of another subset of TGF-β–driven T helper cells,Th17 cells,is highly dependent on de novo lipid biosynthesis.On the basis of these findings,we hypothesized that lipid metabolism may also be important for Th9 cell differentiation.We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1(ACC1),an important enzyme for fatty acid biosynthesis.Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells.Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β–SMAD signaling pathways.Upon adoptive transfer,ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma.Together,our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.展开更多
基金supervised by Osamu Ohara at the Department of Applied Genomics,Kazusa DNA Research Institute and was supported by grants from the Ministry of Education,Culture,Sports,Science and Technology of Japan(Grants-in-Aid:Grant-in-Aid for Scientific Research[B]#20H03455Challenging Research(Exploratory)#20K21618+18 种基金Early-Career Scientists#21K15476 and#22K15502and Young Scientists(Startup)#21K20766)AMED-CREST(JP22gm1810002)from the Japan Agency for Medical Research and DevelopmentFOREST(JPMJFR225X)from JSTTERUMO Life Science FoundationKato Memorial Bioscience FoundationHamaguchi Foundation for the Advancement of BiochemistryTakeda Science FoundationMochida Memorial Foundation for Medical and Pharmaceutical ResearchKishimoto FoundationUehara Memorial FoundationCell Science Research FoundationAstellas Foundation for Research on Metabolic DisordersMSD Life Science FoundationPublic Interest Incorporated FoundationNAGASE Science Technology FoundationCanon FoundationONO Medical Research FoundationPrincess Takamatsu Cancer Research Fund.
文摘T helper 9(Th9)cells are interleukin 9(IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation.Th9 cells differentiate from naïve CD4+T cells in the presence of IL-4 and transforming growth factor-beta(TGF-β);however,our understanding of the molecular basis of their differentiation remains incomplete.Previously,we reported that the differentiation of another subset of TGF-β–driven T helper cells,Th17 cells,is highly dependent on de novo lipid biosynthesis.On the basis of these findings,we hypothesized that lipid metabolism may also be important for Th9 cell differentiation.We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1(ACC1),an important enzyme for fatty acid biosynthesis.Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells.Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β–SMAD signaling pathways.Upon adoptive transfer,ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma.Together,our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.
