Tian Jinmin, Shang Bingli, Zhang Jianing, Guo Yuanyuan, Li Min, Hu Yuechao, Bai Dan, She Junying, Han Yang, Guo Peipei, Huang Mengkun, Wang Yalan, Liu Maoshun, Zhang Jie, Ye Beiwei, Guo Yaxin, Yang Mengjie, Lin Ying, Zhang Ting, Sun Xin, Yuan Xiaoju, Zhang Danni, Xu Ziqian, Chai Yan, Qi Jianxun, Liu Kefang, Tan Shuguang, Zhao Yingze, Zhou Jikun, Song Rui, Gao George F, Liu Jun
National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Nat Immunol. 2025 Feb;26(2):265-278. doi: 10.1038/s41590-024-02051-0. Epub 2025 Jan 28.
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 SNYNYLYRLF, 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 SNYNYRYRLF (Delta/BA.5.2) and SNYDYWYRSF (JN.1), but with immune preservation of SNYDYWYRLF (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.
尽管在新出现的严重急性呼吸综合征冠状病毒2变种中观察到了抗体逃逸现象，但T细胞逃逸，尤其是在BA.2.86/JN.1全球传播之后，尚未得到研究。在此，我们证明在跨越BA.2.86/JN.1突变的表位热点中存在T细胞逃逸。在这个保守的核衣壳蛋白位点新出现的Q229K损害了HLA - A2表位热点识别。HLA - A24康复者与T细胞免疫逃逸之间的关联指向刺突（S）蛋白表位SNYNYLYRLF，从德尔塔毒株到JN.1有多个突变，包括L452Q、L452R、F456L、N450D和L452W，以及N450D、L452W和L455S。观察到针对SNYNYRYRLF（德尔塔/BA.5.2）和SNYDYWYRSF（JN.1）的免疫反应急剧下降，但SNYDYWYRLF（BA.2.86）的免疫反应得以保留。结构分析表明，疏水性暴露决定了L452R和L455S突变体的显著逃逸，这通过T细胞受体结合得到了进一步证实。本研究突出了JN.1的T细胞免疫逃逸特征和分子机制，并从细胞毒性T细胞逃逸的角度为理解变种的优势传播提供了新见解。
