The Immunoregulatory Role of CD244 in Chronic Hepatitis B... : Hepatology (original) (raw)

Viral Hepatitls

The Immunoregulatory Role of CD244 in Chronic Hepatitis B Infection and its Inhibitory Potential on Virus-Specific CD8+ T-cell Function

Raziorrouh, Bijan1; Schraut, Winfried1; Gerlach, Tilman2; Nowack, Daniela1; Gru¨ ner, Norbert H.1; Ulsenheimer, Axel1; Zachoval, Reinhart1; Wa¨chtler, Martin3; Spannagl, Michael4; Haas, Ju¨ rgen5; Diepolder, Helmut M.1; Jung, Maria-Christina1,6

1Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany

2Medical Department, Kantonsspital St. Gallen, St. Gallen, Switzerland

3Medical Department, Klinikum Schwabing, Munich, Germany

4Laboratory of Immunogenetics and Molecular Diagnostics, University Hospital Munich, Munich, Germany

5Centre of Infectious Diseases and Division of Pathway Medicine, University of Edinburgh, Edinburgh, UK

6Leberzentrum, Munich, Germany

A_bbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; APC, allophycocyanin; CFSE, carboxyﬂuorescein succinimidyl ester; EBV, Epstein-Barr virus; FACS, ﬂuorescence-activated cell sorting; FITC, ﬂuorescein isothiocyanate; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeﬁciency virus; HLA, human leukocyte antigen; ICS, intracellular cytokine staining; IL, interleukin; INF, interferon; LIL, liver-inﬁltrating lymphocytes; MFI, mean ﬂuorescence intensity; MHC, major histocompatibility complex; NK, natural killer; PBMC, peripheral blood mononuclear cell; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PE, phycoerythrin; rhIL, recombinant human interleukin; RPMI, Roswell Park Memorial Institute medium; SAP, SLAM-associated protein; SLAM, signaling lymphocyte activation molecule; TIM-3, T-cell immunoglobulin domain and mucin domain 3; TNF-a, tumor necrosis factor a._

Received December 22, 2009; accepted August 15, 2010 1934

View this article online at wileyonlinelibrary.com.

DOI 10.1002/hep.23936

Supported by the Kompetenznetz Hepatitis HepNet (Teilprojekt 10.2.1) (H.D. and M-C.J.), the Research Network ‘‘Natural Resistance to Infection’’ from the

German Federal Ministry of Research (BMBF) (N.G., H.D., B.R., A.U.), and the German Research Foundation (DFG) (A.U., H.D.).

Potential conflict of interest: Nothing to report.

Address reprint requests to: Dr. B. Raziorrouh, Medical Department II, University Hospital Munich-Großhadern, Marchioninistr.15 81377 Munich, Germany. E-mail: [email protected]; fax: 49-89-7095-8887.

Online date: November 9, 2010

Abstract

Multiple inhibitory receptors may play a role in the weak or absent CD81 T-cell response in chronic hepatitis B virus (HBV) infection. Yet few receptors have been characterized in detail and little is known about their complex regulation. In the present study, we investi-gated the role of the signaling lymphocyte activation molecule (SLAM)-related receptor CD244 and of programmed death 1 (PD-1) in HBV infection in 15 acutely and 66 chroni-cally infected patients as well as 9 resolvers and 21 healthy controls. The expression of CD244, PD-1, and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) was an-alyzed in virus-speciﬁc CD81 T-cells derived from peripheral blood or liver using major histocompatibility complex class I pentamers targeting immunodominant epitopes of HBV, Epstein-Barr-virus (EBV), or inﬂuenza virus (Flu). In chronic HBV infection, virus-speciﬁc CD81 T-cells expressed higher levels of CD244 both in the peripheral blood and liver in comparison to the acute phase of infection or following resolution. CD244 was expressed at similarly high levels in EBV infection, but was low on Flu-speciﬁc CD81 T-cells. In chronic HBV infection, high-level CD244 expression coincided with an increased expression of PD-1. The inhibition of the CD244 signaling pathway by antibodies directed against either CD244 or its ligand CD48 resulted in an increased virus-speciﬁc proliferation and cytotoxicity as measured by the expression of CD107a, interferon-c, and tumor necrosis factor-a in CD81 T-cells. Conclusion: CD244 and PD-1 are highly coex-pressed on virus-speciﬁc CD81 T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function independent of the PD-1 pathway. CD244 may thus be another potential target for immunotherapy in chronic viral infec-tions. (HEPATOLOGY 2010;52:1934-1947)