Oral Presentation 14th Lorne Infection and Immunity 2024

Covalent TCR-peptide-MHC interactions: A new mechanism for T cell antigen recognition and T cell activation (#11)

Pirooz Zareie 1 2 , Christopher Szeto 1 3 , Rushika C Wirasinha 1 , Justin Zhang 1 , Andrea T Nguyen 2 3 , Alan Tunnicliffe-Riboldi 4 , Nicole La Gruta 1 , Stephanie Gras 3 , Stephen R Daley 5
  1. Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Instititute, Monash University, Clayton, VIC, Australia
  2. The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  3. Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia
  4. Australian Synchrotron, Australian Nuclear Science and Technology Organisation, Clayton, VIC, Australia
  5. Centre for Immunology and Infection Control, Queensland University of Technology, Brisbane, QLD, Australia

Interactions between a T cell receptor (TCR) and a peptide-major histocompatibility complex (pMHC) ligand are typically mediated by non-covalent bonds. By studying T cells expressing natural or engineered TCRs, here we describe covalent TCR-pMHC interactions that involve a cysteine-cysteine disulphide bond between the TCR and the peptide. By introducing cysteines into a known TCR-pMHC combination, we demonstrate that disulphide bond formation does not require structural rearrangement of the TCR or the peptide. We further show these disulphide bonds still form even when the initial affinity of the TCR-pMHC interaction is low. Accordingly, TCR-peptide disulphide bonds facilitate T cell activation by pMHC ligands with a wide spectrum of affinities for the TCR. Physiologically, this mechanism induces strong Zap70-dependent TCR signalling, which triggers T cell deletion or agonist selection in the thymus cortex. Covalent TCR-pMHC interactions may thus underlie a physiological T cell activation mechanism that has applications in basic immunology and potentially in immunotherapy.