Invited Speaker Australian Society for Microbiology Annual Scientific Meeting 2021

Canonical T cell Receptor Docking on peptide–MHC is essential for an effective antiviral immune response (#73)

Pirooz Zareie 1 , Christopher Szeto 1 , Carine Farenc 1 , Sachith D Gunasinghe 2 , Elizabeth M Kolawole 3 , Angela Nguyen 1 , Chantelle Blyth 1 , Xavier Y. X. Sng 1 , Jasmine Li 4 , Claerwen M Jones 1 , Alex J Fulcher 5 , Jesica R Jacobs 3 , Qianru Wei 6 , Lukasz Wojciech 6 , Jan Peterson 1 7 , Nicholas R. J Gascoigne 6 , Brian D Evevold 3 , Katharina Gaus 2 , Stephanie Gras 1 7 , Jamie Rossjohn 1 7 8 , Nicole L. La Gruta 1
  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. European Molecular Biology Laboratory (EMBL) Australia Node in Single Molecule Science and the ARC Centre of Excellence in Advanced Molecular Imaging, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  3. Department of Pathology, University of Utah, School of Medicine, Salt Lake City, Utah, United States of America
  4. Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  5. Monash Micro Imaging, Monash University, Clayton, VIC, Australia
  6. Immunology Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  7. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia
  8. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom

T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHC) is characterized by a highly conserved docking polarity. Whether the canonical TCR–pMHC polarity is driven by recognition or signaling constraints remains unclear. Using “reversed docking” TRBV17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognize the H-2Db–NP366 epitope of Influenza A virus, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and unrelated to TCR–pMHCI binding. The canonical TCR–pMHCI docking polarity optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed polarity TCR–pMHCI engagement. Thus, a canonical docking topology at the highly diverse TCR–pMHC interface is critical for an effective immune response.