CD8+PD-L1+CXCR3+ polyfunctional T cell abundances are associated with survival in critical SARS-CoV-2–infected patients
Lucille Adam, Pierre Rosenbaum, Paul Quentric, Christophe Parizot, Olivia Bonduelle, Noëlline Guillou, Aurélien Corneau, Karim Dorgham, Makoto Miyara, Charles-Edouard Luyt, Amélie Guihot, Guy Gorochov, Christophe Combadière, Behazine Combadière
Lucille Adam, Pierre Rosenbaum, Paul Quentric, Christophe Parizot, Olivia Bonduelle, Noëlline Guillou, Aurélien Corneau, Karim Dorgham, Makoto Miyara, Charles-Edouard Luyt, Amélie Guihot, Guy Gorochov, Christophe Combadière, Behazine Combadière
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Research Article Immunology

CD8+PD-L1+CXCR3+ polyfunctional T cell abundances are associated with survival in critical SARS-CoV-2–infected patients

Abstract

The importance of the adaptive T cell response in the control and resolution of viral infection has been well established. However, the nature of T cell–mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of patients with COVID-19 in intensive care as a result of phenotypic and functional profiling by mass cytometry. Increased frequencies of circulating, polyfunctional CD4+CXCR5+HLA-DR+ stem cell memory T cells (Tscms) and decreased proportions of granzyme B–expressing and perforin-expressing effector memory T cells were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional PD-L1+CXCR3+CD8+ effector T cells (Teffs), CXCR5+HLA-DR+ Tscms, and anti-nucleocapsid (anti-NC) cytokine-producing T cells permitted us to differentiate between recovered and deceased patients. The results from a principal component analysis show an imbalance in the T cell compartment that allowed for the separation of recovered and deceased patients. The paucity of circulating PD-L1+CXCR3+CD8+ Teffs and NC-specific CD8+ T cells accurately forecasts fatal disease outcome. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefore might impact T cell–based vaccine designs for this infectious disease.

Authors

Lucille Adam, Pierre Rosenbaum, Paul Quentric, Christophe Parizot, Olivia Bonduelle, Noëlline Guillou, Aurélien Corneau, Karim Dorgham, Makoto Miyara, Charles-Edouard Luyt, Amélie Guihot, Guy Gorochov, Christophe Combadière, Behazine Combadière

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Figure 4

Abundance of polyfunctional PD-L1+CXCR3+CD8+ T cells and NC-specific, cytokine-producing T cells define survival vs. fatal outcome after critical SARS-CoV-2 infection.

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Abundance of polyfunctional PD-L1+CXCR3+CD8+ T cells and NC-specific, cy...
PBMCs from critical patients with COVID-19 were incubated with brefeldin A (16 h) and stained using multiparametric mass cytometry panel 2 (n = 21, R = 12, D = 9). (A) CD3+CD8+ T cell (20,000 events) were randomly taken among sample for unsupervised cluster using FlowSOM. Density plot t-SNE representing the expression of indicated markers. (B) Heatmap representation of mean signal intensity of each marker in CD3+CD8+T cell subsets. (C) Density plot t-SNE representing abundance of events using concatenated files of 12 R and 9 D patients. (D) Radar representing mean (min/max normalized) abundances of CD3+CD4+T cell subsets in 12 R (blue) and 9 D (red) patients. Multiple Mann-Whitney U test using Benjamini, Krieger, and Yekutieli FDR correction was performed, with significance set at adjusted P <.05. (E) SARS-CoV-2–specific T cell responses were measured in PBMCs from 46 ICU patients on day 15 ± 0.85 (mean ± SEM) after symptom onset. PBMCs were stimulated for 16 hours with SARS-CoV-2 overlapping 15-mer peptides (S1, S2, and NC). The frequency of specific CD8+ T cells (Boolean gating of IFN-γ, IL-2, and/or TNF-α) is represented with box-and-whisker plots (min to max) after background subtraction according to background control (left). Color-code (green) symbols represent individuals that were under immunosuppressive treatment when SARS-CoV-2–specific responses were studied. Individuals were considered responders when the frequency of cytokines produced was >0.005% of CD3+CD8+ cells. The frequency of nonresponders is represented among R (blue, S1 and S2: n = 31; NC n = 28) and D (red, S1 and S2 n = 15; NC n = 11) patients (right). χ2 test was performed, with significance set at *P < 0.05. (F) Frequency of patients with detectable cells producing cytokines (0, 1, 2, 3 F) after stimulation in R (blue) and D patients (red). χ2 test was performed, with significance set at *P < 0.05. R, recovered; D, deceased; NC, nucleocapsid; F, function.