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.