Mucosal tissue NK cells tune their function between optimal anti-pathogen activity and tissue protection

Abstract

Preserving barrier integrity while mounting effective immunity is essential at mucosal surfaces. In examining the immune cells that mediate both inflammation and tissue homeostasis, we uncovered a dual role for natural killer (NK) cells in barrier immunity. While NK cells are known to control viral infections, here we identify a previously unrecognized reparative function for NK cells in mucosal tissues. Using single-cell RNA sequencing and high-dimensional flow cytometry, we reveal a distinct population of human mucosal NK cells marked by tissue residency, immunoregulatory profiles, and limited cytotoxic potential at homeostasis, yet highly responsive to inflammatory cues. In a mouse model of acute HSV-2 infection, NK cells are required for limiting infection-associated tissue damage. Mucosal NK cells express the epithelial growth factor amphiregulin (Areg), and their depletion leads to increased tissue barrier damage despite preserved viral clearance, suggesting a novel role in tissue protection. Mechanistically, we demonstrate that the barrier-derived cytokines IL-18 and IL-33 induce Areg expression by both human and mouse NK cells, linking local inflammatory cues to reparative NK cell programming that is able to potentiate wound healing. Together, our findings reveal a context-dependent, dual function of mucosal NK cells in immune defense and mucosal tissue protection, expanding current models of NK cell biology.