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

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• SARS-CoV-2 infection can trigger multisystem inflammatory syndrome in children (MIS-C).
• MIS-C shares similarities with superantigen-induced toxic shock syndrome.
• The SARS-CoV-2 spike (S) protein was hypothesized to function as a superantigen, binding T cell receptors (TCRs) to induce T cell responses.

Purpose of the Study:

• To investigate the direct interaction between the SARS-CoV-2 spike protein and T cell receptors (TCRs).
• To experimentally determine if the SARS-CoV-2 spike protein possesses superantigenic properties.

Main Methods:

• Computational modeling to identify potential TCR-binding sites on the S protein.
• Surface plasmon resonance (SPR) to detect direct binding between recombinant S protein and TCRs.
• Pseudotyped lentivirus assays to assess S protein interaction with CD8+ T cells.

Main Results:

• No detectable binding was observed between the SARS-CoV-2 S protein and TCRs using SPR.
• Lentiviruses pseudotyped with the S protein did not transduce, activate, or stimulate proliferation of CD8+ T cells.
• Computational modeling suggested potential binding sites but experimental data did not support direct TCR engagement.

Conclusions:

• The SARS-CoV-2 spike protein is unlikely to act as a superantigen.
• Direct, non-specific engagement of T cell receptors by the spike protein is not supported by experimental evidence.
• The proposed superantigenic mechanism for SARS-CoV-2-induced T cell responses is unlikely.