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

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Mucosal tissues require intact barriers for defense against pathogens and inflammation.
• Natural Killer (NK) cells are vital for controlling viral infections like herpes simplex virus 2 (HSV-2) at barrier sites.
• NK cells must balance pathogen response with the preservation of tissue integrity.

Purpose of the Study:

• To characterize human vaginal tissue (VT) NK cells and their functions.
• To investigate the role of VT NK cells in host protection and tissue repair during HSV-2 infection.
• To validate a mouse model for studying mucosal NK cell responses.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of human VT NK cells.
• High-parameter flow cytometry.
• Acute HSV-2 infection model in mice.

Main Results:

• Human VT NK cells exhibit a unique signature with reduced effector function but enhanced tissue residency and immunoregulation at steady state.
• VT NK cells are poised to respond robustly to inflammatory signals.
• Mouse and human VT NK cells share similar gene signatures, validating the mouse model.
• In mice, VT NK cells responded strongly to HSV-2 infection, showed recall potential, secreted tissue repair factors, and limited tissue damage.

Conclusions:

• Human vaginal tissue NK cells possess distinct characteristics, balancing immune surveillance with tissue protection.
• These NK cells play a critical role in host defense and tissue repair following mucosal viral infection.
• The study highlights an unexpected role for mucosal NK cells in maintaining tissue homeostasis during infection.