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

Manling, X.; Kang, T.; Yusi, Z.; Xiaoyue, X.; Chunmei, Z.; Jiajia, Z.; Fenglan, W.; Xiyue, Z.; Xuyang, Z.; Ran, Z.; Yun, Z.; Boquan, J.; Ma, Y.

doi:10.1101/2024.11.05.622026

bioRxiv · 10.1101/2024.11.05.622026

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

Manling, X.·Kang, T.·Yusi, Z.·Xiaoyue, X.·Chunmei, Z.·Jiajia, Z.·Fenglan, W.·Xiyue, Z.·Xuyang, Z.·Ran, Z.·Yun, Z.·Boquan, J.·Ma, Y.

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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 cytokines 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. Author SummaryHantaan 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 demonstrate that the elevated percentage of CD56dimNKG2A+ NK cell subset in peripheral blood of HFRS patients might exert antiviral effects through the unrecognize between CD94/NKG2A and HLA-E/HTNV peptide complex, which may abrogate the inhibition of NKG2A-expressing NK cells. This study may provide the mechanisms of NKG2A-HLA-E axis on regulating NK cell responses in HTNV infections.

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Manling, X., Kang, T., Yusi, Z., Xiaoyue, X., Chunmei, Z., Jiajia, Z., Fenglan, W., Xiyue, Z., Xuyang, Z., Ran, Z., Yun, Z., Boquan, J., Ma, Y.. 2024-11-07. Hantaan virus-derived peptides that stabilize HLA-E could abrogate inhibition of CD56dimNKG2A+ NK cells. https://doi.org/10.1101/2024.11.05.622026

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