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

• Published in: Science immunology Vol. 6; no. 55
• Main Authors: Kusnadi, Anthony, Ramírez-Suástegui, Ciro, Fajardo, Vicente, Chee, Serena J, Meckiff, Benjamin J, Simon, Hayley, Pelosi, Emanuela, Seumois, Grégory, Ay, Ferhat, Vijayanand, Pandurangan, Ottensmeier, Christian H
• Format: Journal Article
• Language: English
• Published: United States 21.01.2021
• Subjects: Adult; Aged; Aged, 80 and over; CD8-Positive T-Lymphocytes - immunology; COVID-19 - immunology; Female; Glycolysis - immunology; Humans; Immunologic Memory - immunology; Male; Middle Aged; NF-kappa B - immunology; SARS-CoV-2 - immunology; Signal Transduction - immunology; Single-Cell Analysis - methods; Young Adult
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abe4782

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.