Severely ill patients with COVID-19 display impaired exhaustion features in SARS-CoV-2–reactive CD8 ⁺ T cells

Abstract

The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was ‘exhausted’ or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2.

SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 + T cell responses

“…The results of the differential expression analysis on raw counts (|log2 fold-change| > 0.25) are reported in Table S7. Gene signatures for cytotoxic, viral, unhelped, IFN-γ and exhaustion responses were obtained from Kusnadi et al (38), and enrichment was evaluated using R package AUCell (68).…”

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

“…Recent studies have mapped the host immune profiles associated with different stages along the COVID-19 disease trajectory. Reproducible immune correlates of severe COVID-19 include prolonged detection of proinflammatory cytokines such as IL-6, TNFα, and IL-8, diminished type I and type III interferon, and marked lymphopenia, as well as mixed evidence for immune exhaustion and dysfunctional myeloid populations 17–25 . These reports have measured host inflammatory and immune signatures in peripheral blood, which may only partially reflect the immune status within virally targeted tissues 26,27 .…”

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

“…Interestingly these cells exhibited lesser cytotoxic and inflammatory features and could maintain their exhausted state even after viral clearance. In contrast, SARS-CoV-2 reactive CD8 + T cells from patients with severe disease displayed multiple features that support the generation of robust CD8 + T cell memory responses with pro-survival properties and a lack of restraining exhaustion features [399]. To what degree SARS-CoV-2 causes T cell exhaustion and/or impaired T cell memory remains to be determined.…”

“…A longitudinal study of CD8 + T cells during SARS-CoV-2 infections revealed an exhausted phenotype of CD8 + T cells, based on the presence of exhaustion markers including PD-1, CTLA-4, and TIGIT, which, together with reduced poly-functionality according to markers such as IFN-γ, TNF-α, and IL-2 predicted disease severity [396]. However, other studies showed that CD8 + T cells are not exhausted but remain functional [397,398] and a significant proportion of SARS-CoV-2 reactive T cells with "exhausted" phenotype are also found in patients with mild COVID-19 [399]. Interestingly these cells exhibited lesser cytotoxic and inflammatory features and could maintain their exhausted state even after viral clearance.…”