title: Antigen-driven patterns of TCR bias are shared across diverse outcomes of human hepatitis C virus infection.
abstract: Hepatitis C virus (HCV) infection causes significant morbidity and mortality worldwide. T cells play a central role in HCV clearance; however, there is currently little understanding of whether the disease outcome in HCV infection is influenced by the choice of TCR repertoire. TCR repertoires used against two immunodominant HCV determinants--the highly polymorphic, HLA-B*0801 restricted (1395)HSKKKCDEL(1403) (HSK) and the comparatively conserved, HLA-A*0101-restricted, (1435)ATDALMTGY(1443) (ATD)--were analyzed in clearly defined cohorts of HLA-matched, HCV-infected individuals with persistent infection and HCV clearance. In comparison with ATD, TCR repertoire selected against HSK was more narrowly focused, supporting reports of mutational escape in this epitope, in persistent HCV infection. Notwithstanding the Ag-driven divergence, T cell repertoire selection against either Ag was comparable in subjects with diverse disease outcomes. Biased T cell repertoires were observed early in infection and were evident not only in persistently infected individuals but also in subjects with HCV clearance, suggesting that these are not exclusively characteristic of viral persistence. Comprehensive clonal analysis of Ag-specific T cells revealed widespread use of public TCRs displaying a high degree of predictability in TRBV/TRBJ gene usage, CDR3 length, and amino acid composition. These public TCRs were observed against both ATD and HSK and were shared across diverse disease outcomes. Collectively, these observations indicate that repertoire diversity rather than particular Vβ segments are better associated with HCV persistence/clearance in humans. Notably, many of the anti-HCV TCRs switched TRBV and TRBJ genes around a conserved, N nucleotide-encoded CDR3 core, revealing TCR sequence mosaicism as a potential host mechanism to combat this highly variant virus.
authors.affiliation: Queensland Institute of Medical Research, Queensland 4029, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Duangtawan
authors.initials: D
authors.lastname: Thammanichanond
authors.forename: Sarah
authors.initials: S
authors.lastname: Moneer
authors.forename: Usha K
authors.initials: UK
authors.lastname: Nivarthi
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Tracy
authors.forename: Campbell K
authors.initials: CK
authors.lastname: Aitken
authors.forename: Rebekah M
authors.initials: RM
authors.lastname: Brennan
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zeng
authors.forename: Louise
authors.initials: L
authors.lastname: Marquart
authors.forename: David
authors.initials: D
authors.lastname: Jackson
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: David S
authors.initials: DS
authors.lastname: Bowden
authors.forename: Joseph
authors.initials: J
authors.lastname: Torresi
authors.forename: Margaret
authors.initials: M
authors.lastname: Hellard
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Mandvi
authors.initials: M
authors.lastname: Bharadwaj
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis; D014644:Genetic Variation / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D016174:Hepacivirus / Q000276:immunology*; D018963:Hepatitis Antigens / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D016056:Immunodominant Epitopes / Q000276:immunology; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D018963:Hepatitis Antigens; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell