Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C.
Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C.
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DOI：
10.1371/journal.ppat.1003422
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Shoukry NH
中科院分区：
文献类型：
--
作者：
Kared H;Fabre T;Bédard N;Bruneau J;Shoukry NH
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. In this study, we investigated the mechanisms underlying failure of the CD4 helper T cell response during acute hepatitis C infection. 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 Tim-3, PD-1 and 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). In vitro supplementation with IL-21 rescued HCV-specific CD8 T cells from Gal-9 induced apoptosis. Blocking Gal-9 expression in Tregs restored IL-21 production by virus-specific CD4 helper T cells. Altogether, our results suggest that failure of CD4 T cell help during acute HCV may be partially meditated by an imbalance between IL-21-producing CD4 T cells and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway is counteracted by IL-21.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
人白细胞介素17产生的细胞起源于CD161+ CD4+ T细胞前体。
影响因子：
15.3
作者：
Cosmi, Lorenzo;De Palma, Raffaele;Santarlasci, Veronica;Maggi, Laura;Capone, Manuela;Frosali, Francesca;Rodolico, Gabriella;Querci, Valentina;Abbate, Gianfranco;Angeli, Roberta;Berrino, Liberato;Fambrini, Massimiliano;Caproni, Marzia;Tonelli, Francesco;Lazzeri, Elena;Parronchi, Paola;Liotta, Francesco;Maggi, Enrico;Romagnani, Sergio;Annunziato, Francesco
通讯作者：
Annunziato, Francesco
影响因子：
4.4
作者：
Bengsch, Bertram;Seigel, Bianca;Thimme, Robert
通讯作者：
Thimme, Robert
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John
影响因子：
20.3
作者：
Attridge, Kesley;Wang, Chun Jing;Walker, Lucy S. K.
通讯作者：
Walker, Lucy S. K.