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

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<sub>266-274</sub>: 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<sup>+</sup> 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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-08-28
DOI
https://doi.org/10.1038/s41467-025-63288-3
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Rumi Minami, Takashi Toya, Nobuyuki Shimono, Hiroshi Hamana et al.
Nature Communications
SARS-CoV-2 and COVID-19 Research
article

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

Rumi Minami, Takashi Toya, Nobuyuki Shimono, Hiroshi Hamana, Hirotomo Nakata, You Min Ahn, Dhilshan Jayasinghe, Mako Toyoda, Hiroyuki Kishi, Yoshiki Aritsu, Huanyu Li, Chihiro Motozono, Takahito Nakama, Yusuke Tomita, Yan Jin, So Nakagawa, Mizuki Kitamatsu, Yuka Tajima, Demetra S.M. Chatzileontiadou, Takamasa Ueno, Takuro Sakagami, Noritaka Sekiya, Janesha C. Maddumage, Yoshihiko Goto, Stéphanie Gras, Akiko Yonekawa, Yoji Nagasaki
article en

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<sub>266-274</sub>: 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<sup>+</sup> 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.

Nature CommunicationsVol. 16(1)
Tokai University (JP), La Trobe University (AU), National Kyushu Medical Center (JP), Tokyo Metropolitan Komagome Hospital (JP), National Institute of Infectious Diseases (JP), Kyushu University Hospital (JP), Kumamoto University Hospital (JP), University of Toyama (JP), Monash University (AU), Kindai University (JP), Kumamoto University (JP)
Australian Nuclear Science and Technology Organisation, Japan Agency for Medical Research and Development, National Health and Medical Research Council, Japan Society for the Promotion of Science
Openalex Percentile: Top 73%
SARS-CoV-2 and COVID-19 Research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.