Adaptive-like NK cell responses to influenza correlate with humoral immunity and are influenced by age and sex.

Influenza remains a global health threat, infecting approximately one billion people annually and causing significant mortality, particularly among older adults. While hemagglutination inhibition (HAI) antibody titers are a standard correlate of immunity against influenza, they do not reliably predict protection in high-risk populations. Using multiomic single-cell profiling, we identified a distinct subset of adaptive-like NK cells that respond to influenza antigen, predominantly in younger females. These TNFSF10 (+) LGALS9 (+) NK cells exhibit features of adaptive NK cells but lack classical cytomegalovirus-driven markers observed in previous studies. Notably, their increased frequency correlates with high pre-existing HAI titers, suggesting a link between adaptive-like NK responses and humoral immunity. Together, our findings identify an NK subset influenced by age and sex that may contribute to influenza protection, expanding the known diversity of adaptive-like NK cells. These insights could inform future vaccine strategies, particularly for aging populations, by integrating NK responses into assessments of vaccine efficacy.