title: Regulation of HBV-specific CD8(+) T cell-mediated inflammation is diversified in different clinical presentations of HBV infection.
abstract: Chronic HBV infection is the leading cause of liver cirrhosis and hepatic cancer, but the individual responses toward HBV infection are highly variable, ranging from asymptomatic to chronic active hepatitis B inflammation. In this study, we hypothesized that the different individual responses to HBV infection was associated with differences in HBV-specific CD8(+) T cell-mediated inflammation and cytotoxicity. Blood samples were collected from subjects with asymptomatic HBV-infection, subjects undergoing active chronic HBV flares (active CHB), and subjects with HBV-infected hepatocellular carcinoma (HBV-HCC). By tetramer staining, we found that all three groups had similar frequencies of HBVspecific CD8(+) T cells. However, after HBV peptide stimulation, the HBV-specific CD8(+) T cells in asymptomatic subjects had significantly stronger interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and CD107a expression than those in active CHB and HBV-HCC patients. Examination of surface marker expression revealed that the PD-1(-)Tim-3(-) double-negative cell population was the main contributor to HBV-specific inflammation. In active CHB patients and HBV-HCC patients, however, the frequencies of activated PD-1(-)Tim-3(-) cells were significantly reduced. Moreover, the serum HBV DNA titer was not correlated with the frequencies of HBV-specific CD8(+) T cells but was inversely correlated with the frequencies of IFN-g-expressing and CD107a-express cells in response to HBV stimulation. Together, our data demonstrated that the status of HBVspecific CD8(+) T cell exhaustion was associated with different clinical outcomes of chronic HBV infection.
authors.affiliation: Wayne State University Medical Center, Detroit, Michigan, 48201, USA.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dinney
authors.affiliation: Department of Hepatobiliary Surgery, Linyi People's Hospital, Shandong, 276000, P. R. China.
authors.forename: Lu-Dong
authors.initials: LD
authors.lastname: Zhao
authors.affiliation: Wayne State University Medical Center, Detroit, Michigan, 48201, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Conrad
authors.affiliation: Wayne State University Medical Center, Detroit, Michigan, 48201, USA.
authors.forename: Jay M
authors.initials: JM
authors.lastname: Duker
authors.affiliation: Wayne State University Medical Center, Detroit, Michigan, 48201, USA.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Karas
authors.affiliation: Wayne State University Medical Center, Detroit, Michigan, 48201, USA.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Medicine, University of Maryland, Medscientist Group, Baltimore, MD, 21201, USA.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Hamilton
authors.affiliation: Department of Medicine, University of Maryland, Medscientist Group, Baltimore, MD, 21201, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gillis
authors.affiliation: Tufts University, Boston, MA, 02111, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Parker
authors.affiliation: Tufts University, Boston, MA, 02111, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Fan
authors.affiliation: Tufts University, Boston, MA, 02111, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Advani
authors.affiliation: University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Poordad
authors.affiliation: University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
authors.forename: Paulette L
authors.initials: PL
authors.lastname: Fauceglia
authors.affiliation: University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
authors.forename: Kathrin M
authors.initials: KM
authors.lastname: Kirsch
authors.affiliation: Georgetown University, Washington, DC, 20057, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Munk
authors.affiliation: Georgetown University, Washington, DC, 20057, USA.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Ladanyi
authors.affiliation: Georgetown University, Washington, DC, 20057, USA.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Bochner
authors.affiliation: Georgetown University, Washington, DC, 20057, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Bekelman
authors.affiliation: Tufts University, Boston, MA, 02111, USA. CarlaGrandori@itrl.org.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Grandori
authors.affiliation: University of British Columbia, Vancouver, BC, V6T 2B5, Canada. james.olson@mdconnection.ca.
authors.forename: James C
authors.initials: JC
authors.lastname: Olson
authors.affiliation: Georgetown University, Washington, DC, 20057, USA. RonaldLechan@dlpartners.org.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Lechan
authors.affiliation: Department of Medicine, University of Maryland, Medscientist Group, Baltimore, MD, 21201, USA. abougm@medscientist.org.
authors.forename: Ghassan M A
authors.initials: GM
authors.lastname: Abou
authors.affiliation: Department of Medicine, University of Maryland, Medscientist Group, Baltimore, MD, 21201, USA. goodarzima@medscientist.org.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Goodarzi
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004279:DNA, Viral / Q000097:blood; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000276:immunology* / Q000821:virology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D019562:Viral Load; D055815:Young Adult
chemical_list: D004279:DNA, Viral; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D052118:Lysosomal-Associated Membrane Protein 1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: HBV; HCC; PD-1; Tim-3