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

Colonic immune homeostasis is critically maintained by regulatory T (Treg) cells. Here, we identify SUMO-specific peptidase 1 (SENP1) as an important regulator of colonic Treg function and intestinal immune homeostasis. Treg-specific Senp1 deletion does not impair thymic Treg development, but selectively disrupts the homeostasis of colonic Treg subset without affecting Treg maintenance in other peripheral tissues. Mechanistically, SENP1 deficiency reduces CD25 expression on Tregs, blunting IL-2 responsiveness and compromising their expansion and survival. This is associated with a selective reduction in the proportion of tissue-adapted Gata3hi Tregs and accumulation of CD25lo 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.