CD8 ⁺ T cell signature in acute SARS-CoV-2 infection identifies memory precursors

Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen ^1,2 . Since the outbreak of the ongoing coronavirus disease 19 (COVID-19) pandemic, a key question has focused on whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells stimulated during acute infection give rise to long-lived memory T cells ³ . Using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor (TCR) sequencing we longitudinally characterize individual SARS-CoV-2-specific CD8 ⁺ T cells of COVID-19 patients from acute infection to one year into recovery and find a distinct signature identifying long-lived memory CD8 ⁺ T cells. SARS-CoV-2-specific memory CD8 ⁺ T cells persisting one year after acute infection re-express CD45RA and interleukin-7 receptor α (CD127), upregulate T cell factor-1 (TCF1), and maintain low CCR7, thus resembling CD45RA ⁺ effector-memory T (T _EMRA ) cells. Tracking individual clones of SARS-CoV-2-specific CD8 ⁺ T cells, we reveal that an interferon signature marks clones giving rise to long-lived cells, whereas prolonged proliferation and mammalian target of rapamycin (mTOR) signaling are associated with clone contraction and disappearance. Collectively, we identify a transcriptional signature differentiating short-from long-lived memory CD8 ⁺ T cells following an acute virus infection in humans.