9HLJ | pdb_00009hlj

Molecular basis of potent antiviral HLA-C-restricted CD8 + T cell response to an immunodominant SARS-CoV-2 nucleocapsid epitope.

Goto, Y., Ahn, Y.M., Toyoda, M., Hamana, H., Jin, Y., Aritsu, Y., Nakama, T., Tajima, Y., Maddumage, J.C., Li, H., Kitamatsu, M., Kishi, H., Yonekawa, A., Jayasinghe, D., Shimono, N., Nagasaki, Y., Minami, R., Toya, T., Sekiya, N., Tomita, Y., Chatzileontiadou, D.S.M., Nakata, H., Nakagawa, S., Sakagami, T., Ueno, T., Gras, S., Motozono, C.

(2025) Nat Commun 16: 8062-8062

• PubMed: 40877317 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41467-025-63288-3
• Primary Citation of Related Structures:  
  9F13, 9HLJ


• PubMed Abstract: 
  

  The emergence of SARS-CoV-2 Variants of Concern (VOC) is a major clinical threat; however, VOC remain susceptible to cytotoxic T lymphocyte (CTL) recognition. Therefore, it is crucial to identify potent CTL responses targeting conserved epitopes across VOCs. Here, we demonstrate that the nucleocapsid (N) protein induces efficient CTL responses in early pandemic COVID-19 convalescent donors. In the context of the HLA-A24-B52-C12 haplotype, prevalent in Japan, the KF9 peptide (N _266-274 : KAYNVTQAF) is immunodominant and restricted by HLA-C*12:02. KF9-specific T cells are cytotoxic and suppress viral replication of both the ancestral and multiple VOC SARS-CoV-2. KF9-specific CD8 ⁺ T cells maintain effector memory and terminally differentiated phenotypes for 12 months post-infection and proliferate rapidly upon recall. We also determine the structure of a TCR in the context of the HLA-C*12:02-KF9 complex, providing a prototype for the interaction of HLA-C with viral peptides. Surprisingly, despite the TCR's high affinity, the CDR3β loop almost lacks contact with the KF9 peptide. These findings highlight the importance of conserved epitopes and the role of HLA-C molecules in controlling SARS-CoV-2 VOC.

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Organizational Affiliation: 
• Division of Infection and immunity, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, 8600811, Japan.
Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, 8608556, Japan.
Immunity and Infection program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, 3086, Australia.
Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, 3086, Australia.
Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, 9300194, Japan.
Department of Applied Chemistry, Faculty of Science and Engineering, Kindai University, Osaka, 577-8502, Japan.
Center for the Study of Global Infection, Kyushu University Hospital, Kyushu University, Fukuoka, 8128582, Japan.
Division of Infectious Diseases, Clinical Research Institute, National Hospitalization Organization, Kyushu Medical Center, Fukuoka, 8108563, Japan.
Internal Medicine, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, 8108563, Japan.
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, 1138677, Japan.
Department of Infection Prevention and Control, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, 1138677, Japan.
Department of Infectious Disease Emergency Preparedness, Institute of Science Tokyo, Tokyo, 1138510, Japan.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto University Hospital, Kumamoto, 8608556, Japan.
Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, 2591193, Japan.
Immunity and Infection program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, 3086, Australia. S.Gras@latrobe.edu.au.
Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, 3086, Australia. S.Gras@latrobe.edu.au.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia. S.Gras@latrobe.edu.au.
Division of Infection and immunity, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, 8600811, Japan. motozono@kumamoto-u.ac.jp.
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