Canonical T cell receptor docking on peptide-MHC is essential for T cell signaling

Pirooz Zareie; Christopher Szeto; Carine Farenc; Sachith D Gunasinghe; Elizabeth M Kolawole; Angela Nguyen; Chantelle Blyth; Xavier Y X Sng; Jasmine Li; Claerwen M Jones; Alex J Fulcher; Jesica R Jacobs; Qianru Wei; Lukasz Wojciech; Jan Petersen; Nicholas R J Gascoigne; Brian D Evavold; Katharina Gaus; Stephanie Gras; Jamie Rossjohn; Nicole L La Gruta

doi:10.1126/science.abe9124

Canonical T cell receptor docking on peptide-MHC is essential for T cell signaling

Science. 2021 Jun 4;372(6546):eabe9124. doi: 10.1126/science.abe9124.

Authors

Pirooz Zareie¹, Christopher Szeto¹, Carine Farenc¹, Sachith D Gunasinghe², Elizabeth M Kolawole³, Angela Nguyen¹, Chantelle Blyth¹, Xavier Y X Sng¹, Jasmine Li⁴, Claerwen M Jones¹, Alex J Fulcher⁵, Jesica R Jacobs³, Qianru Wei⁶, Lukasz Wojciech⁶, Jan Petersen^{1

7}, Nicholas R J Gascoigne⁶, Brian D Evavold³, Katharina Gaus², Stephanie Gras^#^{8

7}, Jamie Rossjohn^#^{8

7

9}, Nicole L La Gruta^#⁸

Affiliations

¹ Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 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, New South Wales, Australia.
³ Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁴ Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
⁵ Monash Micro Imaging, Monash University, Clayton, Victoria, Australia.
⁶ Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545.
⁷ Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
⁸ Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. [email protected] [email protected] [email protected].
⁹ Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.

^# Contributed equally.

PMID: 34083463
DOI: 10.1126/science.abe9124

Abstract

T cell receptor (TCR) recognition of peptide-major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using "reversed-docking" TCRβ-variable (TRBV) 17⁺ TCRs from the naïve mouse CD8⁺ T cell repertoire that recognizes the H-2D^b-NP₃₆₆ epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR-pMHCI binding or clustering characteristics. Canonical TCR-pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR-pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR-pMHC docking topology is mandated by T cell signaling constraints.

Publication types

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

MeSH terms

Animals
CD3 Complex / metabolism
CD8 Antigens / immunology
CD8 Antigens / metabolism
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
Epitopes, T-Lymphocyte
Female
Histocompatibility Antigen H-2D / chemistry
Histocompatibility Antigen H-2D / immunology
Histocompatibility Antigen H-2D / metabolism*
Influenza A virus
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
Major Histocompatibility Complex
Mice
Mice, Inbred C57BL
Models, Molecular
Nucleocapsid Proteins / chemistry
Nucleocapsid Proteins / immunology
Nucleocapsid Proteins / metabolism*
Orthomyxoviridae Infections / immunology*
Peptide Fragments / immunology
Peptide Fragments / metabolism
Protein Binding
Protein Conformation
Receptors, Antigen, T-Cell, alpha-beta / chemistry
Receptors, Antigen, T-Cell, alpha-beta / immunology
Receptors, Antigen, T-Cell, alpha-beta / metabolism*
Signal Transduction

Substances

CD3 Complex
CD8 Antigens
Epitopes, T-Lymphocyte
Histocompatibility Antigen H-2D
NP protein, Influenza A virus
Nucleocapsid Proteins
Peptide Fragments
Receptors, Antigen, T-Cell, alpha-beta
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)