To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5⁺ T-BET⁺ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8⁺ T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8⁺ T lymphocytes, while CD4⁺ T cells were less expanded and skewed toward T_CM and T_H2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8⁺ GZMB⁺ effector cells were clonally expanded both during the infection and post-infection, while CD8⁺ GZMK⁺ lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8⁺ GZMB⁺ and GZMK⁺ subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8⁺ T cell population with memory precursor-like features.

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