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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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 9

Gradient of function and exhaustion in HCV-specific T cells according to expression of Tim-3 and PD-1.

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Gradient of function and exhaustion in HCV-specific T cells according to...
PD-1–Tim-3– T cells (i) demonstrate a highly polyfunctional profile, with production of antiviral cytokines, cytotoxicity, and phenotype consistent with TEM. Higher frequencies of these cells in acute HCV infection correspond to spontaneous viral eradication. At the other end of the spectrum, PD-1+Tim-3+ T cells (ii) accumulate in early HCV infection prior to development of persistence, demonstrate impaired CD4 help (decreased IL-2 production), impaired ability to secrete antiviral cytokines, and a phenotypic profile consistent with TCM. Initially, TNF-α production is impaired, even though CD8+ T cells maintain the ability to produce IFN-γ (ref. 13 and Figure 4B). The liver contains high expression of the ligands for PD-1 and Tim-3 (PD-L1/PD-L2 and galectin-9, respectively). The intrahepatic T cells express the highest level of PD-1+Tim-3+ T cells, consistent with the most exhausted phenotype, but dual blockade (iii) can restore function in many of these cells, including improved CD107a expression and attendant cytotoxicity.