Broad cross-T cell immunity between emerging SARS-CoV-2 serotypes waved by spike-signature mutations

Since its emergence in late 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has continuously threatened human health through constantly arising variants with iterative immune escape abilities. While SARS-CoV-2 variants have been recently classified into six serotypes based on cross-reactive antibody responses, T cell response features against these serotypes remain largely unknown. We evaluated SARS-CoV-2 spike-specific T cell responses among convalescents infected by three different strains (prototype, BA.5.2/BF.7, and XBB/EG.5.1) against SARS-CoV-2 prototype and 15 subvariants covering all six serotypes. Generally, cross-reactive T cells could recognize variants within the same serotype, but they also mounted weaker responses to variants from subsequent serotypes. Serotype I (prototype) convalescents showed lower T cell responses against Omicron variants (Serotype II to IV), with cross-reactive T cell gaps between different serotype strains, i.e. Serotype II > III > IV. Serotype IV (BA.5.2/BF.7) convalescents exhibited weaker T cell responses to Serotype V (XBB/XBB.1.5/XBB.1.16/EG.5.1) strains and even lower responses to Serotype VI (BA.2.86/JN.1) strains. Similarly, Serotype V (XBB) convalescents showed significantly weaker cross-T cell responses to the Serotype VI (BA.2.86) strains than to the Serotype V strains. We also identified key serotype-signature mutations in T cell epitope hotspot regions that could attenuate CD8+ and/or CD4+ T cell recognition, potentially underlying SARS-CoV-2 serotype-associated T cell immune evasion mechanisms. Our findings reveal the pivotal role of population T cell immune barrier against emerging SARS-CoV-2 variants in a serotype-associated pattern and provide insights into the T cell-oriented universal vaccine development for coronaviruses.自2019年末出现以来，严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）通过不断出现的、具备迭代免疫逃逸能力的变异株持续威胁人类健康。尽管近期研究已基于交叉反应性抗体应答将新冠病毒变异株划分为6种血清型，但针对这些血清型的T细胞应答特征仍未明确。本研究针对感染过三种不同毒株（原型株、BA.5.2/BF.7及XBB/EG.5.1）的康复者，评估了其针对新冠病毒原型株及覆盖全部6种血清型的15种亚变体的刺突蛋白特异性T细胞应答。总体而言，交叉反应性T细胞可识别同一血清型内的变异株，但对后续血清型的变异株的应答强度会有所减弱。I型血清型（原型株）康复者对奥密克戎变异株（II至IV型血清型）的T细胞应答水平较低，且不同血清型毒株间的交叉反应性T细胞应答差距呈现II型＞III型＞IV型的规律。IV型血清型（BA.5.2/BF.7）康复者对V型血清型（XBB/XBB.1.5/XBB.1.16/EG.5.1）毒株的T细胞应答更弱，对VI型血清型（BA.2.86/JN.1）毒株的应答则进一步降低。类似地，V型血清型（XBB）康复者对VI型血清型（BA.2.86）毒株的交叉T细胞应答显著弱于对V型血清型毒株的应答。本研究还在T细胞表位热点区域鉴定出关键的血清型特征突变，这些突变可削弱CD8+和/或CD4+ T细胞的识别能力，这可能是新冠病毒血清型相关T细胞免疫逃逸机制的潜在基础。本研究结果揭示了人群T细胞免疫屏障针对新发新冠病毒变异株的关键作用，且该作用呈现血清型相关模式，同时为面向冠状病毒的T细胞靶向通用疫苗研发提供了新思路。