Antigen-driven patterns of TCR bias are shared across diverse outcomes of human hepatitis C virus infection

Miles, John J., Thammanichanond, Duangtawan, Moneer, Sarah, Nivarthi, Usha K., Kjer-Nielsen, Lars, Tracy, Samantha L., Aitken, Campbell K., Brennan, Rebekah M., Zeng, Weiguang, Marquart, Louise, Jackson, David, Burrows, Scott R., Bowden, David S., Torresi, Joseph, Hellard, Margaret, Rossjohn, Jamie, McCluskey, James, and Bharadwaj, Mandvi (2011) Antigen-driven patterns of TCR bias are shared across diverse outcomes of human hepatitis C virus infection. Journal of Immunology, 186 (2). pp. 901-912.

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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 ¹³⁹⁵HSKKKCDEL¹⁴⁰³ (HSK) and the comparatively conserved, HLA-A*0101-restricted, ¹⁴³⁵ATDALMTGY¹⁴⁴³ (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.

Item ID: 45205
Item Type: Article (Research - C1)
ISSN: 1550-6606
Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Centre for Hepatitis and HIV research (ACHHR), Picchi Brothers Foundation (PBF)
Projects and Grants: NHMRC 331312, NHMRC 208981
Date Deposited: 23 Aug 2016 02:02
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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