Human retinoic acid-regulated CD161⁺ regulatory T cells support wound repair in intestinal mucosa

Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161⁺ regulatory T (T_reg) cells as a distinct, highly suppressive population of T_reg cells that mediate wound healing. These T_reg cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161⁺ T_reg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on T_reg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161⁺ T_reg cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161⁺ T_reg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.