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MINI REVIEW article

Front. Immunol.

Sec. Inflammation

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1672072

This article is part of the Research TopicLipids in ImmunometabolismView all articles

Metabolic Regulation of Th9 Cell Differentiation: Insights for IL-9-Driven Diseases

Provisionally accepted
Swetha  PeesariSwetha PeesariJeremy  P. McAleerJeremy P. McAleer*
  • Marshall University School of Pharmacy, Huntington, United States

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

Th9 cells are a CD4 T cell subset that produces interleukin-9 (IL-9), a pleiotropic cytokine implicated in allergies, autoimmunity and cancer. Defining the cellular effects of IL-9 and factors regulating its expression are essential for fully understanding its roles in immunity and disease. IL-9 acts on a variety of immune and non-immune cells through a heterodimeric receptor composed of IL-9R and the common gamma chain. In CD4 T cells, IL-9 promotes mTOR activation, aerobic glycolysis, proliferation and reinforces its own expression. Additional cellular effects include mast cell activation, B cell antibody production and anti-tumor immunity. These biological activities are complemented by recent studies that expand our understanding of Th9 differentiation beyond canonical cytokine and transcription factor pathways. Notably, glycolytic reprogramming and fatty acid metabolism have emerged as key regulators of IL-9 production, mediated through the activities of mTOR, PPAR- and acetyl-CoA carboxylase 1 (ACC1). mTOR-driven aerobic glycolysis is essential for Th9 cell differentiation, supporting survival, proliferation, and IL9 expression through HIF-1 activation. In contrast, ACC1 suppresses IL-9 through fatty acid synthesis, which enhances RAR-mediated transcriptional repression. PPAR-  appears to have dual functions: it promotes IL-9 production by increasing glucose uptake and activating mTOR, but reduces IL-9 in response to synthetic agonists that may increase fatty acid uptake. Overall, these findings highlight critical roles for metabolic regulators in Th9 responses and suggest that targeting these pathways may offer new therapeutic strategies for IL-9-driven diseases.

Keywords: Th9 cells, Interleukin-9 (IL-9), allergies, Autoimmunity, Cancer, MTOR activation, aerobic glycolysis, proliferation

Received: 23 Jul 2025; Accepted: 01 Sep 2025.

Copyright: © 2025 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, United States

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