SARS-CoV-2 spike does not interact with the T cell receptor or directly activate T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 31; p. e2406615121
• Main Authors: Gaglione, Stephanie A, Rosales, Tatiana J, Schmidt-Hong, Laura, Baker, Brian M, Birnbaum, Michael E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30-07-2024
• Subjects: Binding Sites; Biological Sciences; CD8 antigen; Cell activation; Cell proliferation; Computational neuroscience; COVID-19; COVID-19 - immunology; COVID-19 - virology; HEK293 Cells; Homology; Humans; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Neurotoxins; Protein Binding; Proteins; Receptors; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; SARS-CoV-2 - immunology; SARS-CoV-2 - metabolism; Septic shock; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Surface plasmon resonance; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Toxic shock syndrome; Toxins; superantigen; SARS-CoV-2; T cell receptor
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2406615121

Suggested edit: SARS-CoV-2infection can induce multisystem inflammatory syndrome in children, which resembles superantigen-induced toxic shock syndrome. Recent work has suggested that the SARS-CoV-2 spike (S) protein could act as a superantigen by binding T cell receptors (TCRs) and inducing broad antigen-independent T cell responses. Structure-based computational modeling identified potential TCR-binding sites near the S receptor-binding domain, in addition to a site with homology to known neurotoxins. We experimentally examined the mechanism underpinning this theory-the direct interaction between the TCR and S protein. Surface plasmon resonance of recombinantly expressed S protein and TCR revealed no detectable binding. Orthogonally, we pseudotyped lentiviruses with SARS-CoV-2 S in both wild-type and prefusion-stabilized forms, demonstrated their functionality in a cell line assay, and observed no transduction, activation, or stimulation of proliferation of CD8
T cells. We conclude that it is unlikely that the SARS-CoV-2 spike protein engages nonspecifically with TCRs or has superantigenic character.