NK cell receptor and ligand composition influences the clearance of SARS-CoV-2
Wan-Chen Hsieh, En-Yu Lai, Yu-Ting Liu, Yi-Fu Wang, Yi-Shiuan Tzeng, Lu Cui, Yun-Ju Lai, Hsiang-Chi Huang, Jia-Hsin Huang, Hung-Chih Ni, Dong-Yan Tsai, Jian-Jong Liang, Chun-Che Liao, Ya-Ting Lu, Laurence Jiang, Ming-Tsan Liu, Jann-Tay Wang, Sui-Yuan Chang, Chung-Yu Chen, Hsing-Chen Tsai, Yao-Ming Chang, Gerlinde Wernig, Chia-Wei Li, Kuo-I Lin, Yi-Ling Lin, Huai-Kuang Tsai, Yen-Tsung Huang, Shih-Yu Chen
Wan-Chen Hsieh, En-Yu Lai, Yu-Ting Liu, Yi-Fu Wang, Yi-Shiuan Tzeng, Lu Cui, Yun-Ju Lai, Hsiang-Chi Huang, Jia-Hsin Huang, Hung-Chih Ni, Dong-Yan Tsai, Jian-Jong Liang, Chun-Che Liao, Ya-Ting Lu, Laurence Jiang, Ming-Tsan Liu, Jann-Tay Wang, Sui-Yuan Chang, Chung-Yu Chen, Hsing-Chen Tsai, Yao-Ming Chang, Gerlinde Wernig, Chia-Wei Li, Kuo-I Lin, Yi-Ling Lin, Huai-Kuang Tsai, Yen-Tsung Huang, Shih-Yu Chen
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Research Article

NK cell receptor and ligand composition influences the clearance of SARS-CoV-2

Abstract

To explore how the immune system controls clearance of SARS-CoV-2, we used a single-cell, mass cytometry–based proteomics platform to profile the immune systems of 21 patients who had recovered from SARS-CoV-2 infection without need for admission to an intensive care unit or for mechanical ventilation. We focused on receptors involved in interactions between immune cells and virus-infected cells. We found that the diversity of receptor repertoires on natural killer (NK) cells was negatively correlated with the viral clearance rate. In addition, NK subsets expressing the receptor DNAM1 were increased in patients who more rapidly recovered from infection. Ex vivo functional studies revealed that NK subpopulations with high DNAM1 expression had cytolytic activities in response to target cell stimulation. We also found that SARS-CoV-2 infection induced the expression of CD155 and nectin-4, ligands of DNAM1 and its paired coinhibitory receptor TIGIT, which counterbalanced the cytolytic activities of NK cells. Collectively, our results link the cytolytic immune responses of NK cells to the clearance of SARS-CoV-2 and show that the DNAM1 pathway modulates host-pathogen interactions during SARS-CoV-2 infection.

Authors

Wan-Chen Hsieh, En-Yu Lai, Yu-Ting Liu, Yi-Fu Wang, Yi-Shiuan Tzeng, Lu Cui, Yun-Ju Lai, Hsiang-Chi Huang, Jia-Hsin Huang, Hung-Chih Ni, Dong-Yan Tsai, Jian-Jong Liang, Chun-Che Liao, Ya-Ting Lu, Laurence Jiang, Ming-Tsan Liu, Jann-Tay Wang, Sui-Yuan Chang, Chung-Yu Chen, Hsing-Chen Tsai, Yao-Ming Chang, Gerlinde Wernig, Chia-Wei Li, Kuo-I Lin, Yi-Ling Lin, Huai-Kuang Tsai, Yen-Tsung Huang, Shih-Yu Chen

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Figure 4

SARS-CoV-2 escapes immune surveillance through the DNAM1 paired receptor pathway.

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SARS-CoV-2 escapes immune surveillance through the DNAM1 paired receptor...
(A) Killing efficiency of SARS-CoV-2–infected Calu-1 cells by primary NK cells with or without TIGIT-Fc from 2 independent experiments (n = 6). Maximums, 75th, 50th, 25th percentiles and minimums for TIGIT-Fc alone were 11.40, 10.43, 7.50, 6.10, 4.90; for NK cells alone were 10.70, 10.48, 8.10, 4.50, 2.40; and for NK cells with TIGIT-Fc were 18.10, 17.28, 14.20, 10.88, 9.60, respectively. P = 0.0130 between TIGIT-Fc alone and NK cells with TIGIT-Fc and P = 0.0076 between NK cells alone and NK cells with TIGIT-Fc; Tukey’s multiple comparison test. (B) Box-and-whisker plots of relative CD155 protein (left) and peptide (right) levels in control sera, sera from patients with mild COVID-19, and sera from patients with severe COVID-19. Maximums, 75th, 50th, 25th percentiles and minimums for control, mild COVID-19, and severe COVID-19 in the protein data set were 0.31, –0.07, –0.23, –0.33, and –0.75; 0.18, 0.02, –0.13, –0.25, and –0.59; and 0.45, 0.33, 0.21, –0.09, and –0.21, respectively (n = 72). Values in the peptide data set were 0.61, 0.27, –0.10, –0.27, and –0.58; 0.87, 0.11, –0.11, –0.20, and –0.44; and 1.09, 0.47, 0.30, 0.08, and –0.21, respectively (n = 61). P = 1.03 × 10–5 for protein data set and P = 0.00364 for peptide data set; linear regression. (C) Histogram overlays of percentage of the maximum events for DNAM1 and NKp30 in NK cells from 2 healthy donors versus fluorescence intensity. (D) The efficiencies of killing of pseudovirus-infected A549 cells (target, T) by NK cells from 2 healthy donors (effector, E) at 3 effector/target (E-T) ratios. The means ± SEM for NK cells from healthy donor no. 4 (DNAM1hi and NKp30hi) and healthy donor no. 5 (DNAM1lo and NKp30lo), respectively, were 64.0% ± 1.79% and 34.90% ± 0.40% in 10:1 conditions, 34.78% ± 2.99% and 5.92% ± 1.73% in 2.5:1 conditions, and 14.93% ± 0.93% and 4.91% ± 7.16% in 0.25:1 conditions. P = 0.0225 by linear regression.