# Hantaan virus-derived peptides that stabilize HLA-E could abrogate inhibition of CD56dimNKG2A+ NK cells

## TL;DR

This study shows that Hantaan virus peptides presented by HLA-E can disable the inhibitory signals on certain NK cells, enhancing their antiviral activity in HFRS patients.

## Contribution

The study identifies HTNV-derived peptides that disrupt the NKG2A-HLA-E interaction, revealing a novel mechanism for NK cell activation in viral infections.

## Key findings

- CD56dimNKG2A+ NK cells are the dominant subset in HFRS patients and show activation and cytotoxic potential.
- HTNV peptides presented by HLA-E are not recognized by CD94/NKG2A, leading to abrogated inhibition of NK cells.
- NK cells exhibit increased cytolytic activity against HTNV peptide-pulsed HLA-E cells.

## Abstract

NK cells could participate in the pathogenesis process of virus infectious diseases through the inhibitory receptor CD94/NKG2A interacting with HLA-E/virus-derived peptide complex. However, the effects and mechanisms of NKG2A-HLA-E axis-mediated NK cell responses in hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV) infection remain unclear. Single-cell RNA sequencing and flow cytometry were employed to analyze the phenotype and function of different NK cell subsets in HFRS patients. The K562/HLA-E cells binding assay was used for peptide affinity detection. The binding capacity of HLA-E/peptide-CD94/NKG2A was detected using ligand-receptor binding assay and tetramer staining. The cytotoxicity assay of NK cells against peptide-pulsed K562/HLA-E cells was conducted for functional evaluation. In this study, CD56dimCD16+NKG2A+ NK cells were the main subset in HFRS patients, showing activation and proliferation phenotypes with NKG2C-CD57- and the ability to secrete tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and cytotoxic mediators. Notably, none of the four identified HTNV epitopes presented by HLA-E could be recognized by CD94/NKG2A on CD56dimNKG2A+ NK cells. Furthermore, the subset of CD56dimNKG2A+ NK cells showed the enhanced cytolytic capacity against HTNV peptide pulsed K562/HLA-E cells ex vivo. Taken together, the findings demonstrate that HTNV-derived peptides presented by HLA-E could “abrogate” the inhibition of CD56dimNKG2A+ NK cells, contributing to the antiviral immune response in HFRS patients.

Hantaan virus (HTNV) is one of the main pathogens causing hemorrhagic fever with renal syndrome (HFRS) characterized by fever, hemorrhage, renal injury, and thrombocytopenia. Recently, the studies have shown that the interaction of human leukocyte antigen E (HLA-E) and natural-killer group 2, member A (NKG2A) inhibitory receptors could regulate the functions of NK cells, participating the pathogenesis process of virus infectious diseases. However, the role of NK cell response induced by HTNV infection in the pathogenesis of HFRS has not been completely determined. Here, the findings suggest a potential link between NKG2A-expressing NK cell functional profiles and HTNV infection. The link may be mediated by the mechanism of the lack of recognition between CD94/NKG2A and the HLA-E/HTNV peptide complex. This study may provide the mechanisms of NKG2A-HLA-E axis on regulating NK cell responses in HTNV infections.