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. 2020 Oct 14:11:580237.
doi: 10.3389/fimmu.2020.580237. eCollection 2020.

Elevated Exhaustion Levels of NK and CD8+ T Cells as Indicators for Progression and Prognosis of COVID-19 Disease

Mingyue Li  1 , Weina Guo  1 , Yalan Dong  1 , Xiaobei Wang  2 , Die Dai  3 , Xingxing Liu  1 , Yiquan Wu  4 , Mengmeng Li  5 , Wenjing Zhang  6 , Haifeng Zhou  1 , Zili Zhang  1 , Lan Lin  1 , Zhenyu Kang  1 , Ting Yu  1 , Chunxia Tian  1 , Renjie Qin  1 , Yang Gui  1 , Feng Jiang  7 , Heng Fan  1 , Vigo Heissmeyer  8   9 , Alexey Sarapultsev  10 , Lin Wang  2 , Shanshan Luo  11 , Desheng Hu  1
Affiliations

Elevated Exhaustion Levels of NK and CD8+ T Cells as Indicators for Progression and Prognosis of COVID-19 Disease

Mingyue Li et al. Front Immunol. .

Abstract

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induced Coronavirus Disease 2019 (COVID-19) has posed a global threat to public health. The immune system is crucial in defending and eliminating the virus and infected cells. However, immune dysregulation may result in the rapid progression of COVID-19. Here, we evaluated the subsets, phenotypic and functional characteristics of natural killer (NK) and T cells in patients with COVID-19 and their associations with disease severity.

Methods: Demographic and clinical data of COVID-19 patients enrolled in Wuhan Union Hospital from February 25 to February 27, 2020, were collected and analyzed. The phenotypic and functional characteristics of NK cells and T cells subsets in circulating blood and serum levels of cytokines were analyzed via flow cytometry. Then the LASSO logistic regression model was employed to predict risk factors for the severity of COVID-19.

Results: The counts and percentages of NK cells, CD4+ T cells, CD8+ T cells and NKT cells were significantly reduced in patients with severe symptoms. The cytotoxic CD3-CD56dimCD16+ cell population significantly decreased, while the CD3-CD56dimCD16- part significantly increased in severe COVID-19 patients. More importantly, elevated expression of regulatory molecules, such as CD244 and programmed death-1 (PD-1), on NK cells and T cells, as well as decreased serum cytotoxic effector molecules including perforin and granzyme A, were detected in patients with COVID-19. The serum IL-6, IL-10, and TNF-α were significantly increased in severe patients. Moreover, the CD3-CD56dimCD16- cells were screened out as an influential factor in severe cases by LASSO logistic regression.

Conclusions: The functional exhaustion and other subset alteration of NK and T cells may contribute to the progression and improve the prognosis of COVID-19. Surveillance of lymphocyte subsets may in the future enable early screening for signs of critical illness and understanding the pathogenesis of this disease.

Keywords: COVID-19; T cells; exhaustion; natural killer (NK) cells; prognosis.

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Figures

Figure 1
Figure 1
Alteration of immunologic features of the patients with COVID-19. (A) Counts of peripheral leukocytes from the healthy controls (n = 37), mild cases (n = 16), and severe cases (n = 16). (B) Counts and frequencies of NK cells and T cells from the healthy controls (n = 37), mild cases (n = 16), and severe cases (n = 16). (C) Serum cytokines from the healthy controls (n = 37), mild cases (n = 16), and severe cases (n = 16). The level of significance is indicated as follows: ns, not significant; *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 2
Figure 2
Alteration in the proportion of NK cell subsets and increased levels of regulatory molecules in peripheral blood NK cells from COVID-19 patients. (A) Frequency of NK cell subsets out of CD3- cells among groups. (B) Comparisons of cell expression modules of regulatory molecules (CD244 and PD-1) in NK cells among groups. The level of significance is indicated as follows: ns, not significant; *p <0.05, **p< 0.01, and ***p<0.001.
Figure 3
Figure 3
COVID-19 patients showed an imbalanced proportion of T cell subsets and increased levels of regulatory molecules in peripheral blood T cells. (A) Percentages of CD4+T cells, CD8+T cells and NKT cells of total PBMCs and the ratio of CD4+/CD8+ T cells from the healthy controls (n = 37), mild cases (n = 16), and severe cases (n = 16). (B) Comparisons of cell expression modules of regulatory molecules (CD244, PD-1, and CD27) in CD8+T cells among groups. (C) Comparisons of cell expression modules of regulatory molecules (CD244, PD-1, and CD27) in CD4+T cells among groups. The level of significance is indicated as follows: ns, not significant; *p <0.05, **p< 0.01, and ***p<0.001.
Figure 4
Figure 4
Predictive effect of immune cells and cytokines on the severity of COVID-19 patients. (A) PCA analysis of variable distributions for severe (n = 16) and mild (n = 16) patients. (B) The top 9 factors show a higher contribution to the severity of COVID-19. (C) The AUROC of the LASSO logistic regression model.
Figure 5
Figure 5
Schematic depiction of alterations in NK cells and T cells observed during SARS-CoV-2 infection.
See this image and copyright information in PMC

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