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Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal
Adebowale O Bamidele1, Shravan K Mishra2, Guilherme Piovezani Ramos3
1Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Immunology, Mayo Clinic, Rochester, Minnesota.
Gastroenterology
|January 24, 2024
Summary
Interleukin-21 (IL21) impairs regulatory T cell (Treg) metabolism, promoting inflammation in inflammatory bowel disease. Targeting this IL21-induced metabolic dysfunction in Tregs may treat chronic intestinal inflammation.
Area of Science:
- Immunology
- Cellular Metabolism
- Gastroenterology
Background:
- Incapacitated regulatory T cells (Tregs) are implicated in immune-mediated diseases like inflammatory bowel disease (IBD).
- Mechanisms driving inflammatory Treg development and function in IBD remain poorly understood.
- Cellular metabolism's role in Treg function and gut homeostasis requires further investigation.
Purpose of the Study:
- To investigate the role of cellular metabolism in regulatory T cells (Tregs) relevant to gut homeostasis.
- To understand how metabolic pathways influence Treg function in the context of inflammation.
- To explore potential therapeutic targets for inflammatory Treg-mediated diseases.
Main Methods:
- Utilized human Tregs for mitochondrial ultrastructural studies, biochemical analyses, mass cytometry, metabolomics, and real-time metabolic profiling.
- Employed electron microscopy, confocal imaging, proximity ligation assay, immunoblotting, and Seahorse XF analyzer.
- Analyzed Crohn's disease single-cell RNA sequencing data and tested genetically modified Tregs in murine colitis models.
Main Results:
- Mitochondria-endoplasmic reticulum appositions in Tregs are crucial for pyruvate metabolism; VDAC1 inhibition disrupts this.
- Interleukin-21 (IL21) diminishes these appositions, leading to a hypermetabolic state and amplified Treg inflammatory response.
- IL21-induced metabolic rewiring and inflammation were reversed by methyl pyruvate and a glycogen synthase kinase 3 β inhibitor (LY2090314).
- IL21-induced metabolic genes in Tregs were enriched in human Crohn's disease intestinal Tregs.
- Il21r-/- Tregs demonstrated superior rescue of murine colitis compared to wild-type Tregs.
Conclusions:
- Interleukin-21 (IL21) induces metabolic dysfunction in Tregs, exacerbating their inflammatory response.
- Targeting IL21-induced Treg metabolism offers a potential therapeutic strategy for chronic intestinal inflammation.
- Modulating Treg metabolism presents a promising avenue for treating CD4+ T-cell-driven inflammatory conditions.
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