2. Academic Validation
  3. Metabolic regulation of T cell production of IL-10 and IL-22 protects against intestinal inflammation

Metabolic regulation of T cell production of IL-10 and IL-22 protects against intestinal inflammation

  • Precis Clin Med. 2025 Oct 24;8(4):pbaf025. doi: 10.1093/pcmedi/pbaf025.
Han Liu 1 2,  Xiaojing Zhao 3,  Tianming Yu 1 2 3,  Yu Yu 3,  Suxia Yao 1 2 3,  Wenjing Yang 1 2 3,  Yingzi Cong 1 2 3 4 5
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 2 Center for Human Immunobiology, Northwestern University, Chicago, IL 60611, USA.
  • 3 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 4 Department of Microbiology-Immunology, Northwestern University, Chicago, IL 60611, USA.
  • 5 Department of Pathology, Northwestern University, Chicago, IL 60611, USA.
PMID: 41321963 DOI: 10.1093/pcmedi/pbaf025
Abstract

Objectives: Inflammatory bowel disease is driven by dysregulated CD4⁺ T cell responses to the intestinal microbiota. While T cells can exacerbate inflammation by producing proinflammatory cytokines, they also produce anti-inflammatory mediators, such as interleukin 10 (IL-10) and IL-22. However, the metabolic programs that regulate IL-10 and IL-22 production remain incompletely defined.

Methods: We used CBir1 transgenic mice and in vitro Th1 polarization assays to investigate how metabolic pathways regulate T cell production of IL-10 and IL-22. A panel of metabolic inhibitors was tested for their effects on cytokine expression. Transcriptional mechanisms were assessed using bulk RNA Sequencing, qPCR, Enzyme-linked immunosorbent (ELISA), and CRISPR-Cas9-mediated gene editing. Functional relevance was validated using Citrobacter rodentium Infection and T cell suppression assays in vivo and in vitro.

Results: Among tested metabolic inhibitors, dichloroacetate (DCA) significantly enhanced IL-10 and IL-22 production by CD4⁺ T cells. DCA increased maximal oxygen consumption and decreased lactate secretion in T cells. Mechanistically, DCA upregulated Aryl Hydrocarbon Receptor (Ahr) and downregulated Bhlhe40, without affecting Prdm1. Pharmacologic inhibition of Ahr suppressed DCA-induced IL-22, but not IL-10, while Bhlhe40 knockout enhanced IL-10 production, identifying distinct transcriptional regulators for each cytokine. Functionally, DCA-treated Th1 cells suppressed naïve T cell proliferation via IL-10. In an in vivo experiment, DCA treatment protected mice from C. rodentium-induced colitis.

Conclusions: Our findings demonstrate that DCA enhances IL-22 and IL-10 production in Th1 cells through Ahr and Bhlhe40, respectively. These results identify a novel metabolic mechanism by which DCA promotes mucosal immune regulation and highlight its potential as a therapeutic strategy for inflammatory bowel disease.

Keywords

Ahr; Bhlhe40; IL-10; IL-22; T cell metabolism; dichloroacetate.

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