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

Preserving barrier integrity is of great importance in mucosal tissues while simultaneously defending against inflammatory threats and exposures to pathogens. NK cells at barrier sites are essential for viral control during infections such as herpes simplex virus 2 (HSV-2) but must also balance pathogen response with tissue protection. We have characterized human tissue NK cells in the vaginal tissue (VT) as having distinct effector and tissue protective functions. Using scRNA-seq and high-parameter flow cytometry, we uncovered a unique signature for VT NK cells, indicating a reduced effector phenotype with increased factors related to tissue residency and immunoregulation at steady state. Despite their functionally quiescent nature, these cells were able to respond robustly to inflammatory signals, suggesting they are poised for pathogen response. We found that the gene signatures between mouse and human NK cells were remarkably similar, demonstrating the feasibility of using a mouse model to probe distinct NK cell functions during mucosal infection. In mice, VT NK cells responded robustly to acute HSV-2 infection and retained an enhanced recall potential after viral clearance. They also secreted tissue repair factors and played a role in restricting tissue damage following viral infection. Our data, using both human tissues and a mouse model, reveal an unexpected role of mucosal tissue NK cells in the VT in balancing host protection with tissue repair in the context of localized mucosal tissue infection.