title: Lack of Heterologous Cross-reactivity toward HLA-A*02:01 Restricted Viral Epitopes Is Underpinned by Distinct αβT Cell Receptor Signatures.
abstract: αβT cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. To provide efficient protective anti-viral immunity, a single TCR ideally needs to cross-react with a multitude of pathogenic epitopes. However, the frequency, extent, and mechanisms of TCR cross-reactivity remain unclear, with conflicting results on anti-viral T cell cross-reactivity observed in humans. Namely, both the presence and lack of T cell cross-reactivity have been reported with HLA-A*02:01-restricted epitopes from the Epstein-Barr and influenza viruses (BMLF-1 and M158, respectively) or with the hepatitis C and influenza viruses (NS31073and NA231, respectively). Given the high sequence similarity of these paired viral epitopes (56 and 88%, respectively), the ubiquitous nature of the three viruses, and the high frequency of the HLA-A*02:01 allele, we selected these epitopes to establish the extent of T cell cross-reactivity. We combined ex vivo and in vitro functional assays, single-cell αβTCR repertoire sequencing, and structural analysis of these four epitopes in complex with HLA-A*02:01 to determine whether they could lead to heterologous T cell cross-reactivity. Our data show that sequence similarity does not translate to structural mimicry of the paired epitopes in complexes with HLA-A*02:01, resulting in induction of distinct αβTCR repertoires. The differences in epitope architecture might be an obstacle for TCR recognition, explaining the lack of T cell cross-reactivity observed. In conclusion, sequence similarity does not necessarily result in structural mimicry, and despite the need for cross-reactivity, antigen-specific TCR repertoires can remain highly specific.
authors.affiliation: From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Grant
authors.affiliation: the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, and; the Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Josephs
authors.affiliation: From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Valkenburg
authors.affiliation: the Faculty of Health Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.affiliation: the Center for Research Excellence in Injecting Drug Use, Burnet Institute, Melbourne, Victoria 3004, Australia, and.
authors.forename: Margaret
authors.initials: M
authors.lastname: Hellard
authors.affiliation: the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, and; the Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia,; the Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: Mandvi
authors.initials: M
authors.lastname: Bharadwaj
authors.affiliation: From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia,. Electronic address: kkedz@unimelb.edu.au.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.affiliation: the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, and; the Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia,. Electronic address: Stephanie.Gras@monash.edu.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
mesh_terms: D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D008297:Male; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C488936:M1 protein, Influenza A virus; D010750:Phosphoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090236:SM protein, Human herpesvirus 4; D015534:Trans-Activators; D014763:Viral Matrix Proteins
keywords: Epstein-Barr virus; Hepatitis C virus (HCV); Human Leukocyte Antigen; T cell immunity; cellular immune response; influenza virus; lymphocyte; major histocompatibility complex (MHC); viral immunology