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 5

T cells coexpressing Tim-3 and PD-1 display a TCM phenotype.

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T cells coexpressing Tim-3 and PD-1 display a TCM phenotype. (A and ...
(A and B) CD4+ and CD8+ T cells from acutely infected patients (n = 9) were stained with antibodies against CD45RA, CCR7, and CD27 to determine differentiation phenotype (see Results). (A) Percent PD-1+Tim-3+ cells within each population. Cells expressing both PD-1 and Tim-3 were predominantly of the TCM phenotype. (B) Percent (± SEM) PD-1–Tim-3–, PD-1+Tim-3–, PD-1–Tim-3+, and PD-1+Tim-3+ cells within each population. There were no significant differences in the phenotype of PD-1+Tim-3+ T cells from normal subjects and HCV patients (not shown). (C) CD4+ and CD8+ T cells were stained with antibodies against PD-1, Tim-3, CD69, HLA-DR, and CD45RO, and the PD-1+Tim-3+ and PD-1–Tim-3– phenotypes were compared. Horizontal bars denote means. A significant portion of PD-1+Tim-3+ T cells expressed all 3 activation/memory markers.