Limited T Cell Receptor Diversity of HCV-specific T Cell Responses Is Associated with CTL Escape

Abstract

Escape mutations are believed to be important contributors to immune evasion by rapidly evolving viruses such as hepatitis C virus (HCV). We show that the majority of HCV-specific cytotoxic T lymphocyte (CTL) responses directed against viral epitopes that escaped immune recognition in HCV-infected chimpanzees displayed a reduced CDR3 amino acid diversity when compared with responses in which no CTL epitope variation was detected during chronic infection or with those associated with protective immunity. Decreased T cell receptor (TCR) CDR3 amino acid diversity in chronic infection could be detected long before the appearance of viral escape mutations in the plasma. In both chronic and resolved infection, identical T cell receptor clonotypes were present in liver and peripheral blood. These findings provide a deeper understanding of the evolution of CTL epitope variations in chronic viral infections and highlight the importance of the generation and maintenance of a diverse TCR repertoire directed against individual epitopes.

Immune responses during acute and chronic infection with hepatitis C virus

“…Mutations within CTL epitopes have also been seen in longitudinal studies of acutely infected patients and in single source outbreaks [146; 147; 148; 149] and by population based approaches, which sequence multiple strains and compare the observed patterns of viral variability with the known epitopes recognized in the context of that population's HLA [147; 148; 150]. HCV mutations also affect virus specific CD8+ T cell responses by decreasing binding affinity between epitope and MHC molecule [149], decreasing T cell receptor (TCR) recognition [151] and impairing proteosomal processing of HCV antigens [152]. Mutational escape from CD4+ T cell responses has also been demonstrated [149; 153].…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…Spontaneous resolution of HCV infection has been linked to vigorous and multi-specific T cell responses, while attenuated CD4 + and CD8 + T cell responses have been observed during the chronic phase of viral persistence [3][4][5][6]. Failure to control HCV replication has also been associated with functional defects of virus-specific CD8 + cytotoxic T lymphocytes (CTL) [7][8][9][10] and, most recently, to the appearance of viral escape mutations in immunodominant CD8 + CTL epitopes associated with a lack of or relative defects in HCV-specific CD4 + T cell responses [11][12][13]. Adaptive immune defects during HCV infection are not limited to HCV-specific immune responses and may reflect the broader effects of HCV on the editing of T cell responses also on other antigen specificities [14].…”

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

“…However, the clonal diversity of naive T cells decreases with age (6)(7)(8)(9)(10)(11), resulting in the loss of Ag-specific clones. This leads to a failure of the immune system to recognize certain Ags, including pathogen derived (12), and a higher probability that recognized Ags will subsequently acquire mutations that abrogate their recognition (13). Indeed, in certain strains of mice, as little as a 50% reduction in T cell diversity is sufficient to create large holes in the space of recognized Ags (14), thus impairing their ability to control certain infections.…”