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

Yoshihiko Goto, You Min Ahn, Mako Toyoda, Hiroshi Hamana, Yan Jin, Yoshiki Aritsu, Takeshi Nakama, Yuka Tajima, Janesha C. Maddumage, Huanyu Li, Mizuki Kitamatsu, Hiroyuki Kishi, Akiko Yonekawa, Dhilshan Jayasinghe, Nobuyuki Shimono, Yoji Nagasaki, Rumi Minami, Takashi Toya, Noritaka Sekiya, Yusuke Tomita, Demetra S. M. Chatzileontiadou, Hirotomo Nakata, So Nakagawa, Takuro Sakagami, Takamasa Ueno, Stephanie Gras () and Chihiro Motozono ()
Additional contact information
Yoshihiko Goto: Kumamoto University
You Min Ahn: La Trobe University
Mako Toyoda: Kumamoto University
Hiroshi Hamana: University of Toyama
Yan Jin: Kumamoto University
Yoshiki Aritsu: Kumamoto University
Takeshi Nakama: Kumamoto University
Yuka Tajima: Kumamoto University
Janesha C. Maddumage: La Trobe University
Huanyu Li: Kumamoto University
Mizuki Kitamatsu: Kindai University
Hiroyuki Kishi: University of Toyama
Akiko Yonekawa: Kyushu University
Dhilshan Jayasinghe: La Trobe University
Nobuyuki Shimono: Kyushu University
Yoji Nagasaki: Kyushu Medical Center
Rumi Minami: Kyushu Medical Center
Takashi Toya: Komagome Hospital
Noritaka Sekiya: Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital
Yusuke Tomita: Kumamoto University
Demetra S. M. Chatzileontiadou: La Trobe University
Hirotomo Nakata: Kumamoto University Hospital
So Nakagawa: Tokai University School of Medicine
Takuro Sakagami: Kumamoto University
Takamasa Ueno: Kumamoto University
Stephanie Gras: La Trobe University
Chihiro Motozono: Kumamoto University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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 (N266-274: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63288-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63288-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63288-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().