Fatty acid metabolism constrains Th9 cell differentiation and anti-tumor immunity via modulation of retinoic acid receptor signaling

Abstract

Abstract T helper 9 cells (Th9) are interleukin 9 (IL-9)–producing cells that have diverse functions ranging from anti-tumor immune responses to driving 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 this finding, 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 intracellular fatty acid content and in vivo in mice genetically deficient for acetyl-CoA carboxylase 1 (ACC1), an important enzyme for fatty acid biosynthesis. Both inhibition of de novo fatty acid biosynthesis and deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells. Mechanistic studies revealed that the augmentation of Th9 cell differentiation was mediated by 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.