Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant

T cells are critical in mediating the early control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection. However, it remains unknown whether memory T cells can effectively cross-recognize new SARS-CoV-2 variants with a broad array of mutations, such as the emergent hypermutated BA.2.86 variant. Here, we report in two separate cohorts, including healthy controls and individuals with chronic lymphocytic leukemia, that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection or vaccination demonstrate resilient immune recognition of BA.2.86. In both cohorts, we found largely preserved SARS-CoV-2 spike-specific CD4+ and CD8+ T cell magnitudes against mutated spike epitopes of BA.2.86. Functional analysis confirmed that both cytokine expression and proliferative capacity of SARS-CoV-2 spike-specific T cells to BA.2.86-mutated spike epitopes are similarly sustained. In summary, our findings indicate that memory CD4+ and CD8+ T cells continue to provide cell-mediated immune recognition to highly mutated emerging variants such as BA.2.86. [Display omitted] •SARS-CoV-2 spike-specific T cells are profiled in healthy individuals and CLL patients•T cell cross-recognition of mutated BA.2.86 spike epitopes is largely preserved•BA.2.86-reactive T cells display features of high functional capacity T cells are critical in controlling SARS-CoV-2 infection. The hypermutated BA.2.86 variant exhibits a range of mutations in the spike protein, potentially facilitating evasion from cellular immunity. Müller et al. demonstrate preserved and functional T cell cross-recognition of mutated BA.2.86 epitopes in healthy individuals and patients with chronic lymphocytic leukemia.