Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity

J Clin Invest. 2010 Dec;120(12):4546-57. doi: 10.1172/JCI43127. Epub 2010 Nov 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Blocking / pharmacology
  • Antigens, CD / metabolism*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / metabolism*
  • Case-Control Studies
  • Cell Proliferation
  • Cytotoxicity, Immunologic
  • Female
  • Hepacivirus / immunology*
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / pathology
  • Hepatitis C, Chronic / virology*
  • Humans
  • In Vitro Techniques
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Programmed Cell Death 1 Receptor
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology
  • Up-Regulation
  • Young Adult


  • Antibodies, Blocking
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Membrane Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor