title: T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex.
abstract: Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT(reg)) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT(reg) TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Dennis X
authors.identifier: http://orcid.org/0000-0001-8228-0744
authors.initials: DX
authors.lastname: Beringer
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Fleur S
authors.initials: FS
authors.lastname: Kleijwegt
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Florian
authors.initials: F
authors.lastname: Wiede
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Arno R
authors.initials: AR
authors.lastname: van der Slik
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Khai Lee
authors.identifier: http://orcid.org/0000-0002-2211-2404
authors.initials: KL
authors.lastname: Loh
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Gaby
authors.initials: G
authors.lastname: Duinkerken
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Joosten
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Vivian
authors.affiliation: Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia.|Department of Microbiology &Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Uldrich
authors.affiliation: Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia.|Department of Microbiology &Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.affiliation: Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.|Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia.|School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Radford
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Nikolic
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.|Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D056704:Adaptive Immunity; D017951:Antigen Presentation; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011384:Proinsulin / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D054730:Protein Interaction Domains and Motifs; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D001324:Autoantigens; D015804:HLA-DR4 Antigen; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D011384:Proinsulin