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

Hepatology. 2012 Oct;56(4):1214-22. doi: 10.1002/hep.25771.

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). NKp46(high) NKs were more efficient at controlling HCV than their NKp46(low) 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 NKp46(high) NKs. Cytokine stimulation (interleukin [IL]-12 and IL-15) demonstrated that NKp46(high) NK cells have significantly higher interferon-gamma production than NKp46(low) 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 NKp46(high) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • African Americans / genetics*
  • Apoptosis / genetics
  • Case-Control Studies
  • Cells, Cultured
  • Cytotoxicity, Immunologic / genetics
  • Cytotoxicity, Immunologic / immunology
  • Disease Progression
  • European Continental Ancestry Group / genetics*
  • Female
  • Gene Expression Regulation, Viral
  • Hepacivirus / genetics*
  • Hepacivirus / immunology
  • Hepatitis C, Chronic / ethnology
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / immunology*
  • Hepatocytes / immunology
  • Hepatocytes / physiology
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Male
  • Middle Aged
  • Natural Cytotoxicity Triggering Receptor 1 / genetics*
  • Natural Cytotoxicity Triggering Receptor 1 / immunology
  • Real-Time Polymerase Chain Reaction
  • Reference Values
  • Sensitivity and Specificity
  • Sex Factors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult

Substances

  • Natural Cytotoxicity Triggering Receptor 1
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma