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

Hideki Ogura (), Jin Gohda, Xiuyuan Lu, Mizuki Yamamoto, Yoshio Takesue, Aoi Son, Sadayuki Doi, Kazuyuki Matsushita, Fumitaka Isobe, Yoshihiro Fukuda, Tai-Ping Huang, Takamasa Ueno, Naomi Mambo, Hiromoto Murakami, Yasushi Kawaguchi, Jun-ichiro Inoue, Kunihiro Shirai, Sho Yamasaki, Jun-Ichi Hirata and Satoshi Ishido ()
Additional contact information
Hideki Ogura: Hyogo Medical University
Jin Gohda: The University of Tokyo
Xiuyuan Lu: Osaka University
Mizuki Yamamoto: The University of Tokyo
Yoshio Takesue: Hyogo Medical University
Aoi Son: Hyogo Medical University
Sadayuki Doi: Kawanishi City Hospital
Kazuyuki Matsushita: Kyoritsu Hospital
Fumitaka Isobe: Kyowa Marina Hospital/Wellhouse Nishinomiya
Yoshihiro Fukuda: Dainikyoritsu Hospital
Tai-Ping Huang: Kyoritsu Onsen Hospital
Takamasa Ueno: Kumamoto University
Naomi Mambo: Hyogo Medical University
Hiromoto Murakami: Hyogo Medical University
Yasushi Kawaguchi: The University of Tokyo
Jun-ichiro Inoue: The University of Tokyo
Kunihiro Shirai: Hyogo Medical University
Sho Yamasaki: Osaka University
Jun-Ichi Hirata: Hyogo Medical University
Satoshi Ishido: Hyogo Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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 M198–206 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 M198–206-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.

Date: 2022
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DOI: 10.1038/s41467-022-34655-1

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