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

Vick, S. C.; Domenjo-Vila, E.; Frutoso, M.; Glabman, R. A.; Warrier, L. S.; Hughes, S. M.; Kirby, A. C.; Fialkow, M. F.; Hladik, F.; Prlic, M.; Lund, J. M.

doi:10.1101/2025.04.04.647286

bioRxiv · 10.1101/2025.04.04.647286

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

Vick, S. C.·Domenjo-Vila, E.·Frutoso, M.·Glabman, R. A.·Warrier, L. S.·Hughes, S. M.·Kirby, A. C.·Fialkow, M. F.·Hladik, F.·Prlic, M.·Lund, J. M.

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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.

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Vick, S. C., Domenjo-Vila, E., Frutoso, M., Glabman, R. A., Warrier, L. S., Hughes, S. M., Kirby, A. C., Fialkow, M. F., Hladik, F., Prlic, M., Lund, J. M.. 2025-04-09. Mucosal tissue NK cells tune their function between optimal anti-pathogen activity and tissue protection. https://doi.org/10.1101/2025.04.04.647286

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