Abstract
The dynamics of the memory CD8 T cell receptor (TCR) repertoire upon virus re-exposure and factors governing the selection of TCR clonotypes conferring protective immunity in real life settings are poorly understood. Here, we examined the dynamics and functionality of the virus-specific memory CD8 TCR repertoire before, during and after hepatitis C virus (HCV) reinfection in patients who spontaneously resolved two consecutive infections (SR/SR) and patients who resolved a primary but failed to clear a subsequent infection (SR/CI). The TCR repertoire was narrower prior to reinfection in the SR/SR group as compared to the SR/CI group and became more focused upon reinfection. CD8 T cell clonotypes expanding upon re-exposure and associated with protection from viral persistence were recruited from the memory T cell pool. Individual CD8 T cell lines generated from the SR/SR group exhibited higher functional avidity and polyfunctionality as compared to cell lines from the SR/CI group. Our results suggest that protection from viral persistence upon HCV reinfection is associated with focusing of the HCV-specific CD8 memory T cell repertoire from which established cell lines showed high functional avidity. These findings are applicable to vaccination strategies aiming at shaping the protective human T cell repertoire.
Highlights
The capacity of CD8 T cells to recognize and respond to various pathogen-derived antigens is dictated by the diversity of their T cell receptor (TCR) repertoire
In this study we examined the diversity and dynamics of the repertoire of receptors of CD8 T cells that are selected and enriched upon real-life multiple exposures to viral infections
Using hepatitis C virus (HCV) infection in a cohort of high risk people who inject drugs, we demonstrate that protection upon two subsequent infections was associated with a narrow repertoire of virus-specific CD8 T cells and selective expansion of cells with high polyfunctionality
Summary
The capacity of CD8 T cells to recognize and respond to various pathogen-derived antigens is dictated by the diversity of their T cell receptor (TCR) repertoire. The most variable region in both chains is generated by somatic recombination involving variable (V), junction (J) and diversity (D) gene segments that could theoretically generate ~1015–20 unique TCRs or T-cell clonotypes capable of recognizing peptide-MHC (pMHC) complexes [1]. The CDR3 of the TCR α and β chains, the most variable region of the TCR, are encoded by the V(D)J junction and interact primarily with peptide, determining antigenic specificity of the TCR [1]. Upon exposure to a viral infection, particular clonotypes recognizing virus-derived epitopes/pMHC are selected and expand into primary effectors that contract to form a pool of long-lived memory T cells that are able to respond rapidly upon virus re-exposure. There is evidence to suggest that the memory CD8 T cell repertoire can be modulated by heterologous infections and age [2, 3] but other host and viral factors could be involved
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