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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.

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