Persistent cytolytic CD8+ T cells recognize SARS-CoV-2 and herpesvirus epitopes in long COVID.

Viral-specific CD8+ T cells play roles in protective immunity and immunopathology including during COVID-19. Leveraging combinatorial tetramers, we profiled CD8+ T cells specific for SARS-CoV-2, as well as those for cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-herpesviruses implicated in COVID-19 pathogenesis. During severe COVID-19, EBV-specific CD8+ T cells exhibit a stem-like state, whereas CMV-specific ones are terminally differentiated and cytolytic. Comparing post-acute samples from long COVID (LC) individuals to those recovered revealed that LC-associated CMV-specific CD8+ T cells are T central memory cell (Tcm)- instead of terminally differentiated memory T cell (Temra)-biased. In LC individuals, CD8+ T cells specific for SARS-CoV-2, CMV, and EBV are preferentially terminally differentiated, exhausted, and cytolytic. Cytolytic granzyme-B-expressing CD8+ T cells are particularly prominent among LC women. As granzyme B is upregulated on viral-specific CD8+ T cells during acute viremia, an inability to shut down COVID-19-induced cytolytic effector expression may drive preferential persistence of cytolytic CD8+ T cells in people with LC, which may contribute to LC pathogenesis.