2. Academic Validation
  3. SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly

SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly

  • J Exp Med. 2023 Feb 6;220(2):e20220906. doi: 10.1084/jem.20220906.
Anna Onnis 1,  Emanuele Andreano 2,  Chiara Cassioli 1,  Francesca Finetti 1,  Chiara Della Bella 3,  Oskar Staufer 4,  Elisa Pantano 2,  Valentina Abbiento 2,  Giuseppe Marotta 5,  Mario Milco D'Elios 6,  Rino Rappuoli 2 7,  Cosima T Baldari 1
Affiliations

Affiliations

  • 1 Department of Life Sciences, University of Siena, Siena, Italy.
  • 2 Monoclonal Antibody Discovery Lab, Fondazione Toscana Life Sciences, Siena, Italy.
  • 3 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • 4 Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
  • 5 Siena University Hospital, Siena, Italy.
  • 6 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
  • 7 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
PMID: 36378226 DOI: 10.1084/jem.20220906
Abstract

CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8+ T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. 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. 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). IS defects were also observed ex vivo in CTLs from COVID-19 patients. 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.

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