Viral interactions with B-cells contribute to increased regulatory T-cells during chronic HCV infection

Viral Immunol. 2011 Apr;24(2):119-29. doi: 10.1089/vim.2010.0077.

Abstract

Hepatitis C virus (HCV) has a propensity to establish chronic infection that is characterized by attenuated virus-specific T-cell responses. Mechanisms leading to T-cell attenuation are poorly understood and likely involve dysfunctional interactions between antigen-presenting cells (APC) and effector/regulatory T-cells. Reports on dendritic cells (DC) have described only minor dysfunction during HCV infection. However, there is a paucity of reports regarding B-cell function, despite clear associations with B-cell-related secondary sequelae. In this study we evaluated the state of B-cells during chronic HCV infection, and observed a diminished ability to respond to mitogenic stimuli, correlating with increased apoptosis. This was in contrast to their ex vivo phenotype, which indicated ongoing chronic activation in vivo. There was a high association of HCV-positive strand RNA with B-cells in a subset of HCV patients. Interestingly, ex-vivo-derived HCV RNA-positive B-cells induced significantly greater proliferation in allogeneic T-cells than in HCV-negative B-cells, correlating with an increased generation of CD4(+)CD25(+)FOXP3(+) regulatory T-cells (Tregs). In-vitro exposure of healthy peripheral blood mononuclear cells (PBMC) to HCV resulted in robust activation of resting B-cells. These HCV-exposed B-cells also showed an enhanced ability to generate Tregs. Our results provide strong evidence for a novel and paradoxical link between HCV-induced enhanced APC function and the generation of Tregs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Apoptosis
  • B-Lymphocytes / immunology*
  • CD4 Antigens / analysis
  • Cell Proliferation
  • Female
  • Forkhead Transcription Factors / analysis
  • Hepacivirus / immunology*
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Interleukin-2 Receptor alpha Subunit / analysis
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • T-Lymphocytes, Regulatory / chemistry
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit