Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling.

Autor: Nakajima T; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Kanno T; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Ueda Y; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan., Miyako K; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan.; Department of Applied Genomics, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Endo T; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Yoshida S; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Yokoyama S; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Asou HK; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Yamada K; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Ikeda K; Department of Applied Genomics, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan., Togashi Y; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.; Division of Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan., Endo Y; Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan. endo@kazusa.or.jp.; Department of Omics Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. endo@kazusa.or.jp.
Jazyk: angličtina
Zdroj: Cellular & molecular immunology [Cell Mol Immunol] 2024 Nov; Vol. 21 (11), pp. 1266-1281. Date of Electronic Publication: 2024 Aug 26.
DOI: 10.1038/s41423-024-01209-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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