Queensland Institute of Medical Research, Queensland 4029, Australia.
J Immunol. 2011 Jan 15;186(2):901-12. doi: 10.4049/jimmunol.1003167. Epub 2010 Dec 15.
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-B0801 restricted (1395)HSKKKCDEL(1403) (HSK) and the comparatively conserved, HLA-A0101-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.
丙型肝炎病毒（HCV）感染在全球范围内导致了显著的发病率和死亡率。T 细胞在 HCV 清除中起着核心作用；然而，目前对于 HCV 感染的疾病结局是否受到 TCR 库选择的影响，人们知之甚少。针对两种免疫优势 HCV 决定簇——高度多态性、HLA-B0801 限制（1395）HSKKKCDEL（1403）（HSK）和相对保守、HLA-A0101 限制、（1435）ATDALMTGY（1443）（ATD）——的 TCR 库，在明确定义的 HLA 匹配的、持续感染和 HCV 清除的 HCV 感染个体的队列中进行了分析。与 ATD 相比，针对 HSK 的 TCR 库选择范围更窄，这支持了该表位在持续性 HCV 感染中发生突变逃逸的报告。尽管存在抗原驱动的差异，但在具有不同疾病结局的受试者中，针对这两种抗原的 T 细胞库选择是相当的。在感染早期就观察到了偏向性的 T 细胞库，不仅在持续性感染的个体中，而且在 HCV 清除的个体中也观察到了这一点，这表明这些并不是病毒持续存在的唯一特征。对 Ag 特异性 T 细胞的全面克隆分析显示，广泛使用了具有高度可预测性的公共 TCR，其在 TRBV/TRBJ 基因使用、CDR3 长度和氨基酸组成方面具有高度可预测性。这些公共 TCR 针对 ATD 和 HSK 都有观察到，并且在不同的疾病结局中都有共享。总的来说，这些观察结果表明，与 HCV 持续性/清除相关的是多样性而不是特定的 Vβ 片段。值得注意的是，许多抗 HCV 的 TCR 围绕着一个保守的、N 核苷酸编码的 CDR3 核心，切换了 TRBV 和 TRBJ 基因，这揭示了 TCR 序列镶嵌作为一种潜在的宿主机制，以对抗这种高度变异的病毒。
