Abstract
Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C virus (HCV) infection, but the underlying mechanism(s) remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of HCV-specific CD4 T cells and helper cytokines expression patterns during acute infections with different outcomes. We demonstrate that acute resolving HCV is characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 T cells and increased IL-21 levels in plasma. In contrast, viral persistence was associated with lower frequencies of IL-21-producing CD4 T cells, reduced proliferation and increased expression of the inhibitory receptors T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3), programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on HCV-specific CD8 T cells. Progression to persistent infection was accompanied by increased plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and expansion of Gal-9 expressing regulatory T cells (Tregs). In vitro supplementation of Tim-3high HCV-specific CD8 T cells with IL-21 enhanced their proliferation and prevented Gal-9 induced apoptosis. siRNA-mediated knockdown of Gal-9 in Treg cells rescued IL-21 production by HCV-specific CD4 T cells. We propose that failure of CD4 T cell help during acute HCV is partially due to an imbalance between Th17 and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway may be limited by IL-21 producing Th17 cells or enhanced by Gal-9 producing Tregs.
Highlights
The outcome of acute hepatitis C virus (HCV) infection towards spontaneous resolution or persistent viremia is dictated by the magnitude, breadth and quality of the virus-specific CD4 and CD8 T cell responses [1,2]
We demonstrate that this failure is primarily due to loss of IL-21-producing CD4 T cells in individuals who progress towards chronic infection
This is accompanied by exhaustion of virus-specific cytotoxic CD8 T cells through upregulation of the exhaustion markers T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3), programmed death 1 (PD-1) and cytotoxic Tlymphocyte antigen 4 (CTLA-4), higher plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and increased frequency of Gal-9 producing regulatory T cells (Tregs)
Summary
The outcome of acute hepatitis C virus (HCV) infection towards spontaneous resolution or persistent viremia is dictated by the magnitude, breadth and quality of the virus-specific CD4 and CD8 T cell responses [1,2]. The loss of CD4 helper T cell proliferative responses during acute HCV was associated with viral recurrence and the development of chronic infection [3,4]. CD4 T cell depletion in the chimpanzee model of HCV infection led to persistent low level viremia, the loss of CD8 function and the development of escape mutations in targeted CD8 cytotoxic T lymphocyte (CTL) epitopes [9]. These observations strongly suggest that CD4 helper T cells are critical in sustaining the functions of HCV-specific CD8 T cells. The underlying helper signals and the mechanisms of CD4 T cell failure remain elusive
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