Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV

Paola Fisicaro, Caterina Valdatta, Marco Massari, Elisabetta Loggi, Lara Ravanetti, Simona Urbani, Tiziana Giuberti, Albertina Cavalli, Carmen Vandelli, Pietro Andreone, Gabriele Missale, Carlo Ferrari

Research output: Contribution to journalArticle

Abstract

Background & Aims: In patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, antiviral functions of T cells are impaired; these might be increased by blocking T-cell co-inhibitory pathways, such as preventing interaction between the receptor programmed death (PD)-1 and its ligand, PD-L1. We attempted to optimize the restoration of T-cell functions in patients with chronic HBV or HCV infection with a combination of reagents that block PD-1 interaction with PD-L1 and stimulate T-cell signaling via CD137, a member of the tumor necrosis factor-receptor family. Methods: We assessed the effects of CD137 stimulation (via CD137L), alone or in combination with antibodies that block PD-1 interaction with PD-L1 (anti-PD-L1), on proliferation and production of interferon-γ and interleukin-2 by intrahepatic and peripheral T cells from patients with chronic HBV or HCV infection. We also analyzed expression of different co-stimulatory molecules on virus-specific CD8+ and forkhead box P3+CD4+ cells by flow cytometry. Results: Incubation of intrahepatic T cells with CD137L and anti-PD-L1 increased their responses to HBV, but not HCV. However, HCV-specific T cells isolated from peripheral blood were sensitive to these reagents. Virus-specific T cells from some, but not all patients, had increased responses to anti-PD-L1 when CD137L was added because in some cases the combination of anti-PD-L1 and CD137L overstimulated T cells, leading to their inhibition. Intrahepatic HBV- and HCV-specific CD8+ T cells had different costimulatory profiles; liver cells from patients with chronic HBV infection had a higher proportion of forkhead box P3+ regulatory T cells, with higher levels of PD-1, compared with liver cells from patients with chronic HCV infection. Conclusions: A combination of reagents that prevent interaction between PD-1 and its ligand and activate CD137 signaling increase responses of intrahepatic HBV-specific T cells and circulating HCV-specific T cells. This strategy might be developed to increase T-cell responses to these viruses in patients with chronic hepatitis B or C, and tailoring the dose of CD137L administered will help optimize results.

Original languageEnglish
JournalGastroenterology
Volume143
Issue number6
DOIs
Publication statusPublished - Dec 2012

Keywords

  • IFN
  • IL-2
  • Immune Regulation
  • T-Cell Activation

ASJC Scopus subject areas

  • Gastroenterology

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    Fisicaro, P., Valdatta, C., Massari, M., Loggi, E., Ravanetti, L., Urbani, S., Giuberti, T., Cavalli, A., Vandelli, C., Andreone, P., Missale, G., & Ferrari, C. (2012). Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology, 143(6). https://doi.org/10.1053/j.gastro.2012.08.041