Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection

Abstract

Regulatory T (T R ) cells consist of phenotypically and functionally distinct CD4 + and CD8 + T cell subsets engaged both in maintaining self-tolerance and in preventing anti-non-self effector responses (microbial, tumor, transplant, and so on) that may be harmful to the host.Here we propose that the proinflammatory function of virus-specific memory effector CCR7 -CD8 + T cells, which are massively recruited in the liver, are inefficient (in terms of IFN- production) in patients with chronic hepatitis C virus (HCV) infection because of the concomitant presence of virus-specific CCR7 -CD8 + T R cells producing considerable amounts of IL-10.These CD8 + T R cells are antigen specific, as they can be stimulated by HCV epitopes and suppress T cell responses that are in turn restored by the addition of neutralizing anti-IL-10.This study provides for the first time to our knowledge direct evidence of the existence of virus-specific CD8 + T R cells that infiltrate the livers of patients with chronic HCV infection, identifies IL-10 as a soluble inhibitory factor mediating suppression, and suggests that these cells play a pivotal role in controlling hepatic effector CD8 + T cell responses.Nonstandard abbreviations used: alanine transaminase (ALT); central memory (CM); class I HLA-peptide tetrameric complex (tetramer); hepatitis C virus (HCV); histological activity index (HAI); human plasmacytoid dendritic cells (DC2); indodicarbocyanine (Cy5); liver-infiltrating lymphocyte (LIL); memory effector (ME); nonstructural protein 3 (NS3); phycoerythrin (PE); regulatory T (TR); tricolor (TC).