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

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

T cell metabolism / IL-10 / IL-22 / dichloroacetate / Ahr / Bhlhe40

Acknowledgments

This work was supported by the Crohn’s & Colitis Foundation, award number 1005605, project title STING suppresses colitis through regulation of intestinal barrier function (W.Y.).

Author contributions

Han Liu (Data curation, Formal analysis, Investigation, Validation, Visualization, Writing - original draft, Writing - review & editing), Xiaojing Zhao (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing), Tianming Yu (Data curation, Investigation, Writing - review & editing), Yu Yu (Investigation, Writing - review & editing), Suxia Yao (Investigation, Methodology, Writing - review & editing), Wenjing Yang (Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing), and Yingzi Cong (Conceptualization, Data curation, Methodology, Project administration, Resources, Software, Supervision, Validation, Writing - review & editing).

Supplementary data

Supplementary data is available at PCMEDI Journal online.

Conflict of interest

None declared. In addition, as an Editorial Board Member of Precision Clinical Medicine, the corresponding author Y.C. was blinded from reviewing and making decisions on this manuscript.

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