Metabolic reprogramming of pathogenic CD4+ T helper cells attenuates inflammatory bowel disease in mice, 2026, Mishra et al.

[SNT Gatchaman]

Metabolic reprogramming of pathogenic CD4+ T helper cells attenuates inflammatory bowel disease in mice
Shravan K Mishra; Leena M Abdelrahman; Hyun Se Kim Lee; Lucía Valenzuela-Pérez; Dina F Manna; Tanner J Abram; Lama Mohamed Ali; Heidi M Davidson; Omar M Hassan; William A FaubionJr; Petra Hirsova; Adebowale O Bamidele

CD4+ effector T helper 1 (TH1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence.

We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed TH1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing TH1 cell–associated gene expression.

Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA–dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced TH1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn’s disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4+ T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell–transfer mouse model of colitis.

Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains TH1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.

EDITORS SUMMARY
Pathogenic TH1 cells are a subset of CD4+ T cells that exhibit glycolytic metabolism and produce the cytokine IFN-γ to drive inflammatory conditions, such as colitis. Mishra et al. used methyl pyruvate to force TH1 cells to instead use oxidative phosphorylation, which caused gene expression changes that resulted in the cells being less inflammatory. Glycolytic metabolism in pathogenic TH1 cells was driven by the kinase GSK3β, and treatment of a mouse model of colitis with a GSK3β inhibitor resulted in less severe disease. Together, these findings highlight a GSK3β-dependent metabolic and gene expression profile that supports pathogenic TH1 cell function.

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[SNT Gatchaman]

Cellular metabolism is tightly coupled to T cell fate and function. We showed that effector TH1 cells preferentially engaged aerobic glycolysis while maintaining limited mitochondrial respiration. Forcing mitochondrial pyruvate use by supplementation with MePyr reduced both HK2-dependent glycolysis and acetyl-CoA–dependent histone H3 acetylation at inflammatory gene loci, thereby suppressing cytokine production. Mechanistically, reduced GSK3β activity led to the functional restoration of VDAC1, a GSK3β substrate, and attenuation of HK2-mediated glycolysis with a concomitant increase in OXPHOS.

The immune system senses systemic and tissue metabolic cues to calibrate immune activation. Acetate supplementation partially restored inflammatory cytokine production in MePyr and LY2090314-treated TH1 cells, underscoring the importance of exogenous acetate–derived acetyl-CoA as a substrate for histone acetylation and effector gene expression.

Mechanistically, MePyr-mediated inhibition of GSK3β may converge on canonical T reg cell–associated metabolic pathways, including activation of adenosine monophosphate–activated protein kinase and fatty acid oxidation, processes that are essential for T reg cell differentiation and stability. Whether sustained enhancement of OXPHOS metabolism through MePyr supplementation or GSK3β inhibition can durably rewire TH1 cell epigenetic landscapes in vivo remains unresolved.

In summary, we defined GSK3β as a metabolic checkpoint that integrates microenvironmental cues with intracellular signaling networks to orchestrate metabolism, epigenetic state, and inflammatory TH1 cell phenotype and function.