Bivalent binding of staphylococcal superantigens to the TCR and CD28 triggers inflammatory signals independently of antigen presenting cells

Martina Kunkl; Carola Amormino; Francesco Spallotta; Silvana Caristi; Maria Teresa Fiorillo; Alessandro Paiardini; Raymond Kaempfer; Loretta Tuosto

doi:10.3389/fimmu.2023.1170821

Bivalent binding of staphylococcal superantigens to the TCR and CD28 triggers inflammatory signals independently of antigen presenting cells

Front Immunol. 2023 May 3:14:1170821. doi: 10.3389/fimmu.2023.1170821. eCollection 2023.

Authors

Martina Kunkl¹, Carola Amormino¹, Francesco Spallotta^{1

2}, Silvana Caristi¹, Maria Teresa Fiorillo¹, Alessandro Paiardini³, Raymond Kaempfer⁴, Loretta Tuosto^{1

2}

Affiliations

¹ Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, Rome, Italy.
² Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy.
³ Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Rome, Italy.
⁴ Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Abstract

Staphylococcus aureus superantigens (SAgs) such as staphylococcal enterotoxin A (SEA) and B (SEB) are potent toxins stimulating T cells to produce high levels of inflammatory cytokines, thus causing toxic shock and sepsis. Here we used a recently released artificial intelligence-based algorithm to better elucidate the interaction between staphylococcal SAgs and their ligands on T cells, the TCR and CD28. The obtained computational models together with functional data show that SEB and SEA are able to bind to the TCR and CD28 stimulating T cells to activate inflammatory signals independently of MHC class II- and B7-expressing antigen presenting cells. These data reveal a novel mode of action of staphylococcal SAgs. By binding to the TCR and CD28 in a bivalent way, staphylococcal SAgs trigger both the early and late signalling events, which lead to massive inflammatory cytokine secretion.

Keywords: CD28; T cells; TCR (T cell receptor); inflammation; staphylococcal superantigens.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigen-Presenting Cells / metabolism
Artificial Intelligence
CD28 Antigens*
Receptors, Antigen, T-Cell
Staphylococcus / metabolism
Superantigens*

Substances

Superantigens
CD28 Antigens
Receptors, Antigen, T-Cell

Grants and funding

This research was funded by Sapienza University of Rome, “Progetto Ateneo” to LT, MF and AP, FISM - Fondazione Italiana Sclerosi Multipla, grant number FISM 2020-R-Single/001 to LT, AIRC (Italian Association for Cancer Research) to AP (grant number MFAG 20447) and FS (grant number MFAG 23099), “Ceschina Foundation” to MF.