Vγ9Vδ2 T cells are potent inhibitors of SARS-CoV-2 replication and exert effector phenotypes in COVID-19 patients

Vγ9Vδ2 T cells play a key role in the innate immune response to viral infections, including SARS-CoV-1 and 2, and are activated through butyrophilin (BTN)-3A. Here, the objectives were to: 1) characterize the effects of SARS-CoV-2 infection on the number, phenotype, and activation of Vγ9Vδ2 T cells in infected patients, and 2) assess the effects of in vitro SARS-CoV-2 infection on the expression of BTN3A and its impact on the activation and response of Vγ9Vδ2 T cells to an anti-BTN3A antibody. Blood Vγ9Vδ2 T cells decreased in clinically mild SARS-CoV-2 infections compared to healthy volunteers (HV). This decrease was maintained up to 28 days and in the recovery period. Terminally differentiated Vγ9Vδ2 T cells tend to be enriched on the day of diagnosis, 28 days after and during the recovery period compared to HV. Furthermore, these cells showed cytotoxic and inflammatory activities as shown by TNFα, IFNγ and CD107a/b increase following anti-BTN3A activation. Moreover, BTN3A upregulation and Vγ9Vδ2 T cell infiltration were observed in a lung biopsy from a fatal SARS-CoV-2 infection, as compared to HV. In vitro , SARS-CoV-2 infection significantly increased BTN3A expression in macrophages and lung cell lines. The activation via BTN3A enhanced the anti-SARS-CoV-2 Vγ9Vδ2 T cells cytotoxicity and IFN-γ and TNFα in SARS-CoV-2 infected patient. Increasing concentrations of anti-BTN3A were accompanied by an inhibition of viral replication. Altogether, these data suggest that Vγ9Vδ2 T cells are important in the immune response against SARS-CoV-2 infection and that activation by an anti-BTN3A antibody may enhance their response. KEY POINTS ### Competing Interest Statement D.O is cofounder and shareholder of Imcheck Therapeutics, Emergence Therapeutics, Alderaan Biotechnology and Stealth IO. E.F, L.M, P.F and C.C are employees and shareholders of Imcheck Therapeutics. The other authors declare that they have no competing interests.