Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity
Rachel H. McMahan, … , David R. Gretch, Hugo R. Rosen
Rachel H. McMahan, … , David R. Gretch, Hugo R. Rosen
Published November 15, 2010
Citation Information: J Clin Invest. 2010;120(12):4546-4557. https://doi.org/10.1172/JCI43127.
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Research Article Virology

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

Abstract

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.

Authors

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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Figure 2

Tim-3 expression on HCV-specific CTLs is higher in acute→chronic patients.

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Tim-3 expression on HCV-specific CTLs is higher in acute→chronic patient...
HCV-specific T cell populations were identified by staining with antibodies against CD3, CD8, and a panel of HCV-specific MHC class I pentamers (HLA-A21406, HLA-A22594, and HLA-A11436) along with HLA-A2–rescricted CMV (pp65) pentamer. (A) Representative plots of Tim-3 expression on HCV-specific T cells from 1 acute→chronic and 1 acute→resolved patient. (B and C) Percent pentamer-positive cells expressing Tim-3 (B) and MFI of Tim-3 expression (C) from acute patients (34 responses from 14 patients at 2 time points), long-term chronic patients (13 responses from 11 patients), and remote resolved patients (11 responses from 11 patients). Horizontal bars denote means. Antigen-specific T cells from acute→chronic patients expressed significantly more Tim-3 than did those of acute→resolved patients. A similar expression pattern was seen when comparing long-term chronic with remote resolved patients. Expression of Tim-3 was higher, by both percentage and MFI, on HCV-specific T cells than on CMV-specific T cells in both acute and long-term chronic patients. There was no significant difference in the number of CMV-specific T cells expressing Tim-3 according to HCV outcome.