Antigen-specific memory NK cell responses against HIV and influenza utilize the NKG2/HLA-E axis

For over a decade, multiple studies have disputed the notion of natural
killer (NK) cells as purely innate lymphocytes by demonstrating that they
are capable of putative antigen-specific immunological memory against
multiple infectious agents including two critical global health priorities
– human immunodeficiency virus (HIV) and influenza. However, the
mechanisms underlying antigen specificity remain unknown. Herein, we
demonstrate that antigen-specific human NK cell memory develops upon
exposure to both HIV and influenza, unified by a conserved and
epitope-specific targetable mechanism largely dependent on the activating
CD94/NKG2C receptor and its ligand HLA-E, and confirm these findings by
three rigorous assays. We validated the permanent acquisition of
antigen-specificity by individual memory NK cells by single-cell cloning.
We identified biomarkers of antigen-specific NK cell memory through
complex immunophenotyping by 30-parameter flow cytometry showing elevated
expression of KLRG1, a4b7, and NKG2C. Finally, we show individual
HLA-E-restricted peptides that may constitute the dominant NK cell
response in HIV-1- and influenza-infected persons in vivo. Our findings
clarify the mechanisms behind antigen-specific memory NK cell responses,
and suggest they could be targeted for future vaccines, cure strategies,
or other therapeutic interventions.