V9V2 T-cells Are Potent Inhibitors of SARS-CoV-2 Replication and Represent Effector Phenotypes in Patients With COVID-19

V gamma 9V delta 2 T cells play a key role in the innate immune response to viral infections through butyrophilin 3A (BTN3A). Here, we report blood V gamma 9V delta 2 T cells decreased in clinically mild COVID-19 compared to healthy volunteers, and this was maintained up to 28 days and in the recovery period. Terminally differentiated V gamma 9V delta 2 T cells tended to be enriched on the day of diagnosis, 28 days after, and during the recovery period. These cells showed cytotoxic and inflammatory activities following anti-BTN3A activation. BTN3A upregulation and V gamma 9V delta 2 T-cell infiltration were observed in a lung biopsy from a fatal SARS-CoV-2 infection. In vitro, SARS-CoV-2 infection increased BTN3A expression in macrophages and lung cells that enhanced the anti-SARS-CoV-2 V gamma 9V delta 2 T-cell cytotoxicity and interferon-gamma and tumor necrosis factor-alpha. Increasing concentrations of anti-BTN3A lead to viral replication inhibition. Altogether, we report V gamma 9V delta 2 T cells are important in the immune response against SARS-CoV-2 infection and activation by anti-BTN3A antibody may enhance their response.Clinical Trials Registration. NCT04816760. This study aims to decipher the role of V gamma 9V delta 2 T cells in COVID-19. SARS-CoV-2 mediates upregulation of BTN3A, the V gamma 9V delta 2 T-cell receptor, in lung tissues/cells and mononuclear cells. V gamma 9V delta 2 is differentiated and efficiently degranulated upon activation with BTN3A mAb. Graphical Abstract