Race- and gender-related variation in natural killer p46 expression associated with differential anti-hepatitis c virus immunity

Authors

  • Lucy Golden-Mason,

    1. Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO
    2. Integrated Program in Immunology, University of Colorado Denver and National Jewish Hospital, Denver CO
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  • Amy E.L. Stone,

    1. Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO
    2. Integrated Program in Immunology, University of Colorado Denver and National Jewish Hospital, Denver CO
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  • Kiran M. Bambha,

    1. Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO
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  • Linling Cheng,

    1. Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO
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  • Hugo R. Rosen

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO
    2. Integrated Program in Immunology, University of Colorado Denver and National Jewish Hospital, Denver CO
    3. Denver VA Medical Center, Denver, CO.
    • Division of Gastroenterology and Hepatology, University of Colorado Denver, B-158, Academic Office Building 1, 12631 East 17th Avenue, Room 7614, P.O. Box 6511, Aurora, CO 80045
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    • fax: 303-724-1891


  • Potential conflict of interest: Nothing to report.

  • The authors thank Dr. Takaji Wakita (National Institute of Infectious Diseases) for kindly providing the JFH-1 plasmid. The authors thank the Colorado Center for AIDS Research Laboratory Core for access to FACS sorting.

Abstract

Major racial and gender differences have been documented in the natural history and treatment responses of chronic hepatitis C virus (HCV) infection; however, distinct mechanisms have remained enigmatic. We hypothesized that racial- and gender-related differences in natural killer (NK) cell populations may explain altered natural history and treatment responses. Our study cohort consisted of 29 African-American (AA; 55% male) and 29 Caucasian-American (CA; 48% male) healthy uninfected control subjects. Multiparameter flow cytometric analysis was used to characterize levels, phenotype with respect to 14 NK receptors, and lymphokine-activated killing (LAK) function. Gene expression was assessed by real-time reverse-transcriptase polymerase chain reaction after 6-hour in vitro stimulation with Toll-like receptor (TLR) ligands. The ability to control HCV infection was assessed in the Huh-7.5/JFH-1 coculture system. NK expression of natural cytotoxicity receptor NKp46 was strongly associated with CA race and female gender and correlated positively with LAK activity (P = 0.0054). NKp46high NKs were more efficient at controlling HCV than their NKp46low counterparts (P < 0.001). Similarly, ligation of NKp46 on isolated NK cells resulted in a significant reduction in the HCV copy number detected in Huh-7.5/JFH-1 coculture (multiplicity of infection: 0.01) at an effector:target ratio of 5:1 (P < 0.005). After TLR stimulation, genes involved in cytotoxicity, but not cytokine genes, were significantly up-regulated in NKp46high NKs. Cytokine stimulation (interleukin [IL]-12 and IL-15) demonstrated that NKp46high NK cells have significantly higher interferon-gamma production than NKp46low cells. TLR stimulation significantly induced degranulation as well as tumor necrosis factor alpha (TNF-α)-related apoptosis-inducing ligand, Fas, and TNF-α protein expression in NKp46high NKs. NKp46 ligand was induced on HCV-infected hepatocytes. Conclusions: NKp46 expression may contribute to differential HCV responses. NKp46 expression correlates with anti-HCV activity in vitro and thus may prove to be a useful therapeutic target. (HEPATOLOGY 2012)

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