Nrf2 suppresses inflammatory Th1/Th17 responses and promotes regulatory T cell differentiation by CD4⁺ T cells to alleviate ulcerative colitis

Introduction/Rationale: Ulcerative colitis (UC) is a chronic, relapsing form of inflammatory bowel disease (IBD) characterized by inflammation of the colon driven by an imbalance between proinflammatory and regulatory CD4⁺ T-cell subsets. Nrf2 (nuclear factor erythroid 2–related factor 2), a master regulator of oxidative stress responses, has emerged as a key modulator of immune cell function, but its role in regulating CD4⁺ T-cell differentiation and intestinal inflammation remains unclear.

Methods: To elucidate the role of Nrf2 in T-cell–mediated ulcerative colitis (UC), we used transgenic mice with T cell–specific deletion of Nrf2 (Nrf2-KO; no Nrf2) or Keap1 (Keap1-KO; high Nrf2). The effects of altered Nrf2 activity on CD4⁺ T-cell differentiation were examined using in vitro polarization assays, while disease outcomes were assessed using an adoptive transfer model of colitis, in which naïve CD4⁺ T cells from WT or Keap1-KO mice were transferred into immunodeficient Rag1⁻/⁻ mice. Single cell RNAseq data from the colons of UC patients was analyzed to identify gene signatures.

Results: CD4⁺ T cells with elevated Nrf2 activity (Keap1-KO) showed reduced differentiation into inflammatory Th1 and Th17 subsets and enhanced differentiation and function of Foxp3⁺ regulatory T cells (Tregs). In the adoptive transfer model, high Nrf2 activity in CD4⁺ T cells markedly alleviated colonic inflammation and reduced disease severity. Mechanistically, Nrf2 enhanced glutamine metabolism in induced Tregs, promoting oxidative phosphorylation and increased Foxp3 expression. Consistently, colonic CD4⁺ T cells from UC patients with higher Nrf2 expression exhibited lower inflammatory gene signatures.

Conclusion: These findings demonstrate that Nrf2 suppresses pathogenic Th1/Th17 responses while promoting regulatory T-cell differentiation and metabolic fitness, thereby alleviating colitis. T cell–intrinsic activation of Nrf2 represents a promising therapeutic strategy for treating UC and other inflammatory disorders of the gut.