SENP1 facilitates the adaptation of colonic non-lymphoid tissue Treg cells and restrains intestinal inflammation

precursor-like Tregs in the intestinal lamina propria. Senp1 depletion also downregulates core effector Treg signature genes including Gata3, Klrg1, and Il1rl1, correlating with dysregulated Th2 response control. Single-cell RNA sequencing analysis reveals transcriptional alterations consistent with impaired colonic Treg tissue adaptation after SENP1 ablation. Functionally, with adoptive transfer experiments we found that Senp1-deficient Tregs show impaired accumulation in vivo and are associated with weaker control of pathogenic T cell expansion in the colon. Consistently, Treg-specific Senp1-deficient mice display heightened susceptibility to DSS-induced colitis, highlighting a critical role of SENP1 in sustaining functional Treg programs and limiting pathogenic intestinal inflammation.