Single-cell transcriptomics reveal a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19

Chuang Guo; Mingming Wu; Beibei Huang; Rui Zhao; Linlin Jin; Binqing Fu; Ping Wang; Dongyao Wang; Meijuan Zheng; Jingwen Fang; Haiming Wei; Kun Qu; Fang Ni

doi:10.1186/s13073-022-01049-3

Single-cell transcriptomics reveal a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19

Genome Med. 2022 May 3;14(1):46. doi: 10.1186/s13073-022-01049-3.

Authors

Chuang Guo^#^{1

2}, Mingming Wu^#¹, Beibei Huang^#², Rui Zhao¹, Linlin Jin¹, Binqing Fu^{1

3}, Ping Wang¹, Dongyao Wang³, Meijuan Zheng⁴, Jingwen Fang², Haiming Wei^{5

6}, Kun Qu^{7

8}, Fang Ni^{9

10}

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
² Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
³ Institute of Immunology, University of Science and Technology of China, Hefei, China.
⁴ Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁵ Department of Hematology, The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. ustcwhm@ustc.edu.cn.
⁶ Institute of Immunology, University of Science and Technology of China, Hefei, China. ustcwhm@ustc.edu.cn.
⁷ Department of Hematology, The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. qukun@ustc.edu.cn.
⁸ Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. qukun@ustc.edu.cn.
⁹ Department of Hematology, The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. fangni@ustc.edu.cn.
¹⁰ Institute of Immunology, University of Science and Technology of China, Hefei, China. fangni@ustc.edu.cn.

^# Contributed equally.

Abstract

Background: Natural killer (NK) cells are innate lymphoid cells that mediate antitumour and antiviral responses. However, very little is known about how ageing influences human NK cells, especially at the single-cell level.

Methods: We applied single-cell sequencing (scRNA-seq) to human lymphocytes and NK cells from 4 young and 4 elderly individuals and then analysed the transcriptome data using Seurat. We detected the proportion and phenotype of NK cell subsets in peripheral blood samples from a total of 62 young and 52 elderly healthy donors by flow cytometry. We also used flow cytometry to examine the effector functions of NK cell subsets upon IFN-α/IL-12+IL-15/K562/IL-2 stimulation in vitro in peripheral blood samples from a total of 64 young and 63 elderly healthy donors. We finally studied and integrated single-cell transcriptomes of NK cells from 15 young and 41 elderly COVID-19 patients with those from 12 young and 6 elderly healthy control individuals to investigate the impacts of ageing on NK cell subsets in COVID-19 disease.

Results: We discovered a memory-like NK subpopulation (NK2) exhibiting the largest distribution change between elderly and young individuals among lymphocytes. Notably, we discovered a unique NK subset that was predominantly CD52⁺ NK2 cells (NK2.1). These memory-like NK2.1 cells accumulated with age, exhibited proinflammatory characteristics, and displayed a type I interferon response state. Integrative analyses of a large-cohort COVID-19 dataset and our datasets revealed that NK2.1 cells from elderly COVID-19 patients are enriched for type I interferon signalling, which is positively correlated with disease severity in COVID-19.

Conclusions: We identified a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19. Our results identify memory-like NK2.1 cells as a potential target for developing immunotherapies for infectious diseases and for addressing age-related dysfunctions of the immune system.

Keywords: Ageing; COVID-19; NK cell; Single-cell RNA-seq; Type-I interferon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aging / genetics
COVID-19*
Humans
Immunity, Innate
Killer Cells, Natural / metabolism
Severity of Illness Index
Transcriptome*