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<p>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 <i>HLA-A24-B52-C12</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月28日

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  • 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,
  • Chihiro Motozono

摘要

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.