Nrf2 suppresses inflammatory Th1/Th17 responses and promotes regulatory T cell differentiation by CD4+ T cells to alleviate ulcerative colitis 2260871

Abstract Introduction 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. Funding Source This work was supported by startup funds by the University of Kansas Cancer Center (KUCC). We acknowledge the support and funds from Kansas Institute for Precision Medicine (NIGMS P20 GM130423). Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)