A selective decrease in cytotoxic T lymphocytes (CTL) in the upper respiratory tract has been observed in patients with severe disease compared to patients with milder disease ( Chua et al., 2020). Interestingly, CD8 + T cells appear preferentially dysregulated in severe COVID-19 compared with CD4 + T cells. T cell defects include lymphopenia and dysfunctions that range from excessive activation and exhaustion to defective activation and abnormalities in differentiation ( Chen and John Wherry, 2020 Kalfaoglu et al., 2021). Severe coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with immune dysregulation, with defective IFN type I response ( Bastard et al., 2020 Zhang et al., 2020), local hyperactivation of innate immune cells, impaired adaptive immune responses, and a prominent role for T cells ( Chen and John Wherry, 2020 Kalfaoglu et al., 2021). These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent elimination of infected cells. IS defects were also observed ex vivo in CTLs from COVID-19 patients. These defects were reversed by anti-Spike antibodies interfering with ACE2 binding and reproduced by ACE2 engagement by angiotensin II or anti-ACE2 antibodies, but not by the ACE2 product Ang (1-7). CTL preincubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing and cytokine production. We show that human CD8 + T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS).
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