Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19

• Published in: Nature communications Vol. 13; no. 1; pp. 7063 - 15
• Main Authors: Ogura, Hideki, Gohda, Jin, Lu, Xiuyuan, Yamamoto, Mizuki, Takesue, Yoshio, Son, Aoi, Doi, Sadayuki, Matsushita, Kazuyuki, Isobe, Fumitaka, Fukuda, Yoshihiro, Huang, Tai-Ping, Ueno, Takamasa, Mambo, Naomi, Murakami, Hiromoto, Kawaguchi, Yasushi, Inoue, Jun-ichiro, Shirai, Kunihiro, Yamasaki, Sho, Hirata, Jun-Ichi, Ishido, Satoshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 49/91; 631/1647/514/1949; 631/250/1619/554/1775; 631/250/255/2514; 631/326/596/4130; Antigen-presenting cells; Antigens; Antiviral agents; Antiviral drugs; CD8 antigen; CD8-Positive T-Lymphocytes; Cell differentiation; Coronaviruses; COVID-19; Cytotoxicity; Epitopes; Epitopes, T-Lymphocyte; Gene expression; Gene sequencing; Histocompatibility antigen HLA; HLA-A Antigens; Humanities and Social Sciences; Humans; Identification methods; Immune clearance; Immune response; Immune system; Lymphocytes; Lymphocytes T; M protein; multidisciplinary; Phenotypes; Proteins; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Structural proteins; T-Lymphocytes, Cytotoxic; Viral diseases; Viruses; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34655-1

Although the importance of virus-specific cytotoxic T lymphocytes (CTL) in virus clearance is evident in COVID-19, the characteristics of virus-specific CTLs related to disease severity have not been fully explored. Here we show that the phenotype of virus-specific CTLs against immunoprevalent epitopes in COVID-19 convalescents might differ according to the course of the disease. We establish a cellular screening method that uses artificial antigen presenting cells, expressing HLA-A * 24:02, the costimulatory molecule 4-1BBL, SARS-CoV-2 structural proteins S, M, and N and non-structural proteins ORF3a and nsp6/ORF1a. The screen implicates SARS-CoV-2 M protein as a frequent target of IFNγ secreting CD8 + T cells, and identifies M 198–206 as an immunoprevalent epitope in our cohort of HLA-A * 24:02 positive convalescent COVID-19 patients recovering from mild, moderate and severe disease. Further exploration of M 198–206 -specific CD8 + T cells with single cell RNA sequencing reveals public TCRs in virus-specific CD8 + T cells, and shows an exhausted phenotype with less differentiated status in cells from the severe group compared to cells from the moderate group. In summary, this study describes a method to identify T cell epitopes, indicate that dysfunction of virus-specific CTLs might be an important determinant of clinical outcomes. Cytotoxic T lymphocytes play important roles in the anti-viral immune response in COVID-19, and it is important to know how they contribute to disease outcome. Authors here identify a dominant SARS-CoV-2 M protein epitope, M 198–206 , and show that M 198–206 -specific cytotoxic T cells from convalescent patients with severe disease harbour a gene expression pattern indicative of poor functionality.