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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1509408
This article is part of the Research Topic Immune Cell Metabolism Beyond Energy Supply – An Emerging Era to Showcase Novel Roles in Immune Effector Functions View all articles

Regulation of Human Th9 Cell Differentiation by Lipid Modulators Targeting PPAR-γ and Acetyl-CoA-carboxylase 1

Provisionally accepted
Swetha Peesari Swetha Peesari Jeremy P. McAleer Jeremy P. McAleer *
  • Marshall University School of Pharmacy, Huntington, WV, United States

The final, formatted version of the article will be published soon.

    T cell activation induces dramatic changes to cellular metabolism to support their growth and differentiation into effector cells. Here, we show that modulators targeting central regulators of lipid metabolism regulate human Th9 cell differentiation in vitro. Culturing naïve CD4 T cells from healthy donors with the combination of IL-4, TGF- and IL-21 induced robust IL-9 production and PPARG expression. The PPAR- agonist rosiglitazone substantially decreased IL-9 production, whereas the inhibitor GW9662 had no significant effect, demonstrating that thiazolidinediones suppress Th9 cell differentiation. Rosiglitazone also suppressed IL-9 in the presence of the glucose metabolism inhibitor 2-deoxy-D-glucose, suggesting the suppressive effect on Th9 differentiation was independent of glycolysis. Next, the role of fatty acid synthesis was tested by treating cells with inhibitors of acetyl-CoA-carboxylase 1 (ACC1; TOFA) or AMP-activated protein kinase (AMPK; dorsomorphin). We demonstrate reciprocal functions for these enzymes, as ACC1 inhibition substantially increased IL-9 production, whereas AMPK inhibition resulted in undetectable levels. Providing exogenous oleic acid to TOFA-treated cultures restored IL-9 back to the levels in control Th9 cultures, suggesting that ACC1 suppresses Th9 differentiation through fatty acid synthesis. Overall, our data demonstrate that lipid regulators associated with intracellular fatty acid accumulation suppress Th9 cell differentiation.

    Keywords: Th9 cells, IL-9, ACC1 acetyl-CoA carboxylase 1, PPAR-gamma, CD4 T cell

    Received: 10 Oct 2024; Accepted: 10 Dec 2024.

    Copyright: © 2024 Peesari and McAleer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jeremy P. McAleer, Marshall University School of Pharmacy, Huntington, WV, United States

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