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<p>Although antibody escape is observed in emerging severe acute respiratory syndrome coronavirus 2 variants, T cell escape, especially after the global circulation of BA.2.86/JN.1, is unexplored. Here we demonstrate that T cell evasion exists in epitope hotspots spanning BA.2.86/JN.1 mutations. The newly emerging Q229K at this conserved nucleocapsid protein site impairs HLA-A2 epitope hotspot recognition. The association between HLA-A24 convalescents and T cell immune escape points to the spike (S) protein epitope S<sub>448–456</sub>NYNYLYRLF, with multiple mutations from Delta to JN.1, including L452Q, L452R, F456L, N450D and L452W, and N450D, L452W and L455S. A cliff drop of immune responses was observed for S<sub>448–456</sub>NYNYRYRLF (Delta/BA.5.2) and S<sub>448–456</sub>NY<Emphasis Type="Underline">D</Emphasis>Y<Emphasis Type="Underline">W</Emphasis>YR<Emphasis Type="Underline">S</Emphasis>F (JN.1), but with immune preservation of S<sub>448–456</sub>NY<Emphasis Type="Underline">D</Emphasis>Y<Emphasis Type="Underline">W</Emphasis>YRLF (BA.2.86). Structural analyses showed that hydrophobicity exposure determines the pronounced escape of L452R and L455S mutants, which was further confirmed by T cell receptor binding. This study highlights the characteristics and molecular mechanisms of the T cell immune escape for JN.1 and provides new insights into understanding the dominant circulation of variants, from the viewpoint of cytotoxic T cell evasion.</p>

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T cell immune evasion by SARS-CoV-2 JN.1 escapees targeting two cytotoxic T cell epitope hotspots

  • 期刊论文

  • 发表日期：

    2025年1月28日

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  • Jinmin Tian,
  • Bingli Shang,
  • Jianing Zhang,
  • Yuanyuan Guo,
  • Min Li,
  • Yuechao Hu,
  • Dan Bai,
  • Junying She,
  • Yang Han,
  • Peipei Guo,
  • Mengkun Huang,
  • Yalan Wang,
  • Maoshun Liu,
  • Jie Zhang,
  • Beiwei Ye,
  • Yaxin Guo,
  • Mengjie Yang,
  • Ying Lin,
  • Ting Zhang,
  • Xin Sun,
  • Xiaoju Yuan,
  • Danni Zhang,
  • Ziqian Xu,
  • Yan Chai,
  • Jianxun Qi,
  • Kefang Liu,
  • Shuguang Tan,
  • Yingze Zhao,
  • Jikun Zhou,
  • Rui Song,
  • George F. Gao,
  • Jun Liu

摘要

Although antibody escape is observed in emerging severe acute respiratory syndrome coronavirus 2 variants, T cell escape, especially after the global circulation of BA.2.86/JN.1, is unexplored. Here we demonstrate that T cell evasion exists in epitope hotspots spanning BA.2.86/JN.1 mutations. The newly emerging Q229K at this conserved nucleocapsid protein site impairs HLA-A2 epitope hotspot recognition. The association between HLA-A24 convalescents and T cell immune escape points to the spike (S) protein epitope S448–456NYNYLYRLF, with multiple mutations from Delta to JN.1, including L452Q, L452R, F456L, N450D and L452W, and N450D, L452W and L455S. A cliff drop of immune responses was observed for S448–456NYNYRYRLF (Delta/BA.5.2) and S448–456NYDYWYRSF (JN.1), but with immune preservation of S448–456NYDYWYRLF (BA.2.86). Structural analyses showed that hydrophobicity exposure determines the pronounced escape of L452R and L455S mutants, which was further confirmed by T cell receptor binding. This study highlights the characteristics and molecular mechanisms of the T cell immune escape for JN.1 and provides new insights into understanding the dominant circulation of variants, from the viewpoint of cytotoxic T cell evasion.