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In-depth analysis of SARS-CoV-2–specific T cells reveals diverse differentiation hierarchies in vaccinated individuals
Li Li, Muharrem Muftuoglu, Shaoheng Liang, Mahesh Basyal, Jiangxing LV, Mehmet Emin Akdogan, Ken Chen, Michael Andreeff, Christopher R. Flowers, Simrit Parmar
Li Li, Muharrem Muftuoglu, Shaoheng Liang, Mahesh Basyal, Jiangxing LV, Mehmet Emin Akdogan, Ken Chen, Michael Andreeff, Christopher R. Flowers, Simrit Parmar
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Research Article COVID-19 Immunology

In-depth analysis of SARS-CoV-2–specific T cells reveals diverse differentiation hierarchies in vaccinated individuals

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Abstract

SARS-CoV-2 vaccines pose as the most effective approach for mitigating the COVID-19 pandemic. High-degree efficacy of SARS-CoV-2 vaccines in clinical trials indicates that vaccination invariably induces an adaptive immune response. However, the emergence of breakthrough infections in vaccinated individuals suggests that the breadth and magnitude of vaccine-induced adaptive immune response may vary. We assessed vaccine-induced SARS-CoV-2 T cell response in 21 vaccinated individuals and found that SARS-CoV-2–specific T cells, which were mainly CD4+ T cells, were invariably detected in all individuals but the response was varied. We then investigated differentiation states and cytokine profiles to identify immune features associated with superior recall function and longevity. We identified SARS-CoV-2–specific CD4+ T cells were polyfunctional and produced high levels of IL-2, which could be associated with superior longevity. Based on the breadth and magnitude of vaccine-induced SARS-CoV-2 response, we identified 2 distinct response groups: individuals with high abundance versus low abundance of SARS-CoV-2–specific T cells. The fractions of TNF-α– and IL-2–producing SARS-CoV-2 T cells were the main determinants distinguishing high versus low responders. Last, we identified that the majority of vaccine-induced SARS-CoV-2 T cells were reactive against non-mutated regions of mutant S-protein, suggesting that vaccine-induced SARS-CoV-2 T cells could provide continued protection against emerging variants of concern.

Authors

Li Li, Muharrem Muftuoglu, Shaoheng Liang, Mahesh Basyal, Jiangxing LV, Mehmet Emin Akdogan, Ken Chen, Michael Andreeff, Christopher R. Flowers, Simrit Parmar

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Figure 2

SARS-CoV-2 vaccination induces a CD4+ T cell–dominant immune response.

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SARS-CoV-2 vaccination induces a CD4+ T cell–dominant immune response.
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(A) Representative FACS plots summarize cytokine production (TNF-α, IL-2, and IFN-γ) from CD4+ and CD8+ T cells in 1 of 21 donors. (B) The bubble plot shows the percentage of TNF-α–, IL-2–, and IFN-γ–secreting CD4+ and CD8+ T cells in 21 vaccinated individuals. The colors indicate cytokine and the size represents cytokine percentage per CD4 or CD8. (C) The bar plot shows the frequency of SARS-CoV-2–specific CD4+ and CD8+ T cells. Error bars represent mean ± SEM. (*P < 0.05 by Wilcoxon paired t test, n = 21.) (D) The relative percentages of SARS-CoV-2–specific CD4+ and CD8+ T cells in 13 individuals having detectable SARS-CoV-2–specific CD8+ T cells. (E) UMAP dimension and clusters identify differential response to vaccination (left). Volcano plot (right) shows the differentially expressed cytokines between C1 and C2 (Mann-Whitney U test, n = 21). (F) Plots show the comparison of SARS-CoV-2–specific T cells and IgG antibody level between low and high responders (*P < 0.05, **P < 0.01, unpaired t test, n = 21). Plots show the frequencies of SARS-CoV-2–specific T cells (CD4+ and CD8+) and the levels of S-protein–specific IgG. (G) The Spearman’s correlation matrices of immune features extracted from 21 vaccinated individuals (*P < 0.05, **P < 0.01, ***P < 0.001,****P < 0.0001, Wilcoxon paired t test, n = 21).

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