Inhibitory Molecules That Regulate Expansion and Restoration of HCV-Specific CD4(+) T Cells in Patients With Chronic Infection

Bijan Raziorrouh, Axel Ulsenheimer, Winfried Schraut, Malte Heeg, Peter Kurktschiev, Reinhart Zachoval, Maria-Christina Jung, Robert Thimme, Christoph Neumann-Haefelin, Sophia Horster, Martin Waechtler, Michael Spannagl, Juergen Haas, Helmut M. Diepolder, Norbert H. Gruener

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND & AIMS: Inhibitory receptors such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen (CTLA)-4 mediate CD8(+) T-cell exhaustion during chronic viral infection, but little is known about roles in dysfunction of CD4(+) T cells. METHODS: We investigated the functions of inhibitory molecules on hepatitis C virus (HCV)-, influenza-, and Epstein-Barr virus (EBV)-specific CD4(+) T cells in patients with chronic infections compared with patients with resolved HCV infection and healthy donors. Expression of PD-1, CTLA-4, CD305, and CD200R were analyzed on HCV-specific CD4(+) T cells, isolated from peripheral blood using major histocompatibility complex class II tetramers. We investigated the effects of in vitro inhibition of various inhibitory pathways on proliferation and cytokine production by CD4(+) T cells, and we compared these effects with those from inhibition of interleukin (IL)-10 and transforming growth factor (TGF)-beta 1. RESULTS: PD-1 and CTLA-4 were up-regulated on virus-specific CD4(+) T cells from patients with chronic HCV infections. PD-1 expression was lower on influenza-than on HCV-specific CD4(+) T cells from subjects with chronic HCV infection, whereas CTLA-4 was expressed at similar levels, independent of their specificity. CD305 and CD200R were up-regulated in HCV resolvers. Blockade of PD-L1/2, IL-10, and TGF-beta 1 increased expansion of CD4(+) T cells in patients with chronic HCV, whereas inhibition of IL-10 and TGF-beta 1 was most effective in restoring HCV-specific production of interferon gamma, IL-2, and tumor necrosis factor alpha. CONCLUSIONS: We characterized expression of inhibitory molecules on HCV-, influenza-, and EBV-specific CD4(+) T cells and the effects of in vitro blockade on CD4(+) T-cell expansion and cytokine production. Inhibition of PD-1, IL-10, and TGF-beta 1 is most efficient in restoration of HCV-specific CD4(+) T cells.

Original languageEnglish
Pages (from-to)1422-U891
Number of pages16
JournalGastroenterology
Volume141
Issue number4
DOIs
Publication statusPublished - Oct 2011

Keywords

  • IFN-GAMMA
  • TNF
  • Immune Regulation
  • Antiviral Response

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