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Nat Commun
. 2025 Aug 28;16(1):8062.
doi: 10.1038/s41467-025-63288-3. Molecular basis of potent antiviral HLA-C-restricted CD8+ T cell response to an immunodominant SARS-CoV-2 nucleocapsid epitope
Yoshihiko Goto # 1 2 , You Min Ahn # 3 4 , Mako Toyoda 1 , Hiroshi Hamana 5 , Yan Jin 1 , Yoshiki Aritsu 1 , Takeshi Nakama 1 , Yuka Tajima 1 2 , Janesha C Maddumage 3 4 , Huanyu Li 1 , Mizuki Kitamatsu 6 , Hiroyuki Kishi 5 , Akiko Yonekawa 7 , Dhilshan Jayasinghe 3 4 , Nobuyuki Shimono 7 , Yoji Nagasaki 8 , Rumi Minami 9 , Takashi Toya 10 , Noritaka Sekiya 11 12 , Yusuke Tomita 2 , Demetra S M Chatzileontiadou 3 4 13 , Hirotomo Nakata 14 , So Nakagawa 15 , Takuro Sakagami 2 , Takamasa Ueno 1 , Stephanie Gras 16 17 18 , Chihiro Motozono 19
Affiliations
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.
. 2025 Aug 28;16(1):8062.
doi: 10.1038/s41467-025-63288-3. Molecular basis of potent antiviral HLA-C-restricted CD8+ T cell response to an immunodominant SARS-CoV-2 nucleocapsid epitope
Yoshihiko Goto # 1 2 , You Min Ahn # 3 4 , Mako Toyoda 1 , Hiroshi Hamana 5 , Yan Jin 1 , Yoshiki Aritsu 1 , Takeshi Nakama 1 , Yuka Tajima 1 2 , Janesha C Maddumage 3 4 , Huanyu Li 1 , Mizuki Kitamatsu 6 , Hiroyuki Kishi 5 , Akiko Yonekawa 7 , Dhilshan Jayasinghe 3 4 , Nobuyuki Shimono 7 , Yoji Nagasaki 8 , Rumi Minami 9 , Takashi Toya 10 , Noritaka Sekiya 11 12 , Yusuke Tomita 2 , Demetra S M Chatzileontiadou 3 4 13 , Hirotomo Nakata 14 , So Nakagawa 15 , Takuro Sakagami 2 , Takamasa Ueno 1 , Stephanie Gras 16 17 18 , Chihiro Motozono 19
Affiliations
- PMID: 40877317
- DOI: 10.1038/s41467-025-63288-3
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.