Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C.
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...
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doaj-26252d426c93441dbde7c80d12d087b92020-11-25T01:34:03ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-01-0196e100342210.1371/journal.ppat.1003422Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C.Hassen KaredThomas FabreNathalie BédardJulie BruneauNaglaa H ShoukryLoss 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-3(high) 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.http://europepmc.org/articles/PMC3688567?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hassen Kared Thomas Fabre Nathalie Bédard Julie Bruneau Naglaa H Shoukry |
spellingShingle |
Hassen Kared Thomas Fabre Nathalie Bédard Julie Bruneau Naglaa H Shoukry Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathogens |
author_facet |
Hassen Kared Thomas Fabre Nathalie Bédard Julie Bruneau Naglaa H Shoukry |
author_sort |
Hassen Kared |
title |
Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. |
title_short |
Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. |
title_full |
Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. |
title_fullStr |
Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. |
title_full_unstemmed |
Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. |
title_sort |
galectin-9 and il-21 mediate cross-regulation between th17 and treg cells during acute hepatitis c. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2013-01-01 |
description |
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-3(high) 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. |
url |
http://europepmc.org/articles/PMC3688567?pdf=render |
work_keys_str_mv |
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