| Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. | |
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MedLine Citation:
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PMID: 21084749 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Having successfully developed mechanisms to evade immune clearance, hepatitis C virus (HCV) establishes persistent infection in approximately 75%-80% of patients. In these individuals, the function of HCV-specific CD8+ T cells is impaired by ligation of inhibitory receptors, the repertoire of which has expanded considerably in the past few years. We hypothesized that the coexpression of the negative regulatory receptors T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) and programmed death 1 (PD-1) in HCV infection would identify patients at risk of developing viral persistence during and after acute HCV infection. The frequency of PD-1-Tim-3- HCV-specific CTLs greatly outnumbered PD-1+Tim-3+ CTLs in patients with acute resolving infection. Moreover, the population of PD-1+Tim-3+ T cells was enriched for within the central memory T cell subset and within the liver. Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by Tim-3 blockade. These results indicate that the coexpression of these inhibitory molecules tracks with defective T cell responses and that anatomical differences might account for lack of immune control of persistent pathogens, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches. |
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Authors:
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Rachel H McMahan; Lucy Golden-Mason; Michael I Nishimura; Brian J McMahon; Michael Kemper; Todd M Allen; David R Gretch; Hugo R Rosen |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-11-15 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 120 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-02 Completed Date: 2011-01-14 Revised Date: 2012-05-08 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 4546-57 Citation Subset: AIM; IM |
Affiliation:
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Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado Denver, Denver, Colorado, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Aged, 80 and over Antibodies, Blocking / pharmacology Antigens, CD / metabolism* Apoptosis Regulatory Proteins / antagonists & inhibitors, metabolism* Case-Control Studies Cell Proliferation Cytotoxicity, Immunologic Female Hepacivirus / immunology* Hepatitis C, Chronic / immunology*, pathology, virology* Humans Male Membrane Proteins / antagonists & inhibitors, metabolism* Middle Aged Programmed Cell Death 1 Receptor T-Lymphocyte Subsets / immunology, pathology T-Lymphocytes, Cytotoxic / immunology*, pathology Up-Regulation Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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K24 AI083742/AI/NIAID NIH HHS; K24 AI083742-03/AI/NIAID NIH HHS; R01 AI 066209/AI/NIAID NIH HHS; R01 DK060590/DK/NIDDK NIH HHS; U19 A1066328//PHS HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Blocking; 0/Antigens, CD; 0/Apoptosis Regulatory Proteins; 0/HAVCR2 protein, human; 0/Membrane Proteins; 0/PDCD1 protein, human; 0/Programmed Cell Death 1 Receptor |
| Comments/Corrections | |
Comment In:
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Hepatology. 2011 Nov;54(5):1879-82
[PMID:
22038790
]
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Erratum In:
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J Clin Invest. 2011 Feb 1;121(2):821 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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