Abstract

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 Treg 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, ROR gamma t, 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.