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

Author ORCID

Stephanie Jost 0000-0003-2100-3262

Taylor Yoder 0009-0002-6077-5206

Kyle Kroll 0000-0002-9237-9497

Sho Sugawara 0000-0002-5187-423X

George Tweet 0009-0004-7811-1744

Haley Dugan 0000-0003-2238-0094

Joshua Ghofrani 0000-0002-5956-9096

Michaela Müller-Trutwin 0000-0002-3854-2396

Paul Goepfert 0000-0001-8441-5737

R. Keith Reeves 0000-0003-3157-2557

Publication Date

5-24-2024

Abstract

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.

Keywords

natural killer cell, HIV, Influenza

Repository

Dryad

Distribution License

CC0 1.0 Universal - No copyright; this work is in the public domain

Link to Dataset

Share

COinS