CD56 bright NK IL-7Rα expression negatively associates with HCV level, and IL-7-induced NK function is impaired during HCV and HIV infections

J Leukoc Biol. 2017 Jul;102(1):171-184. doi: 10.1189/jlb.5A1116-456R. Epub 2017 Apr 11.

Abstract

Several lines of evidence support the concept that NK cells play an important role in control of hepatitis C virus (HCV) infection via cytokine secretion and cytotoxicity. IL-7 is a homeostatic cytokine with a role in T cell development, activation, proliferation, and cytokine secretion. The IL-7Rα chain [cluster of differentiation (CD)127] is expressed on NK cells, with greatest abundance on the CD56brightCD16dim/- (CD56bright) subset. Here, we measured CD127 expression on CD56bright, CD56dimCD16+ (CD56dim), or CD56negCD16+ (CD56neg) NK cell subsets of 25 uninfected donors (UD); 34 chronic HCV-infected, treatment-naïve; 25 HIV-infected, virally suppressed on antiretroviral therapy (ART); and 42 HCV-HIV-coinfected subjects on ART. Interestingly, CD127 expression on CD56bright NK cells negatively correlated with HCV plasma levels in HCV monoinfection and HCV-HIV coinfection. IL-7 induced CD69 expression, as well as IFN-γ production, in CD56bright NK cells and also enhanced the IFN-α-induced CD69 expression on these cells. The latter was impaired in HIV infection. Furthermore, IL-7 induced B cell lymphoma 2 (BCL-2) expression and cell cycling of CD56bright NK cells, and this effect was impaired in HCV- and HIV-infected subjects. Whereas IL-7-stimulated CD56bright NK cell degranulation appeared intact in all cohorts, we observed impaired IL-7-activated NK cell cytolytic function in HCV- and HIV-infected subjects. Finally, IL-7-induced phosphorylation of STAT-5 (pSTAT-5) signaling was impaired in NK cells of subjects with chronic viral infection, and this was reversible upon 6 mo of viral suppression with IFN-free HCV therapy. These results implicate that IL-7-dependent NK cell activation and effector function may be other host immune surveillance mechanisms that are impaired in viral infections.

Keywords: IFN-γ; cellular immunity; host defense; innate immunity; viral immunity.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / immunology
  • CD56 Antigen / immunology*
  • Female
  • Gene Expression Regulation / immunology*
  • HIV Infections / immunology*
  • HIV Infections / pathology
  • HIV Infections / therapy
  • HIV-1 / immunology
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / pathology
  • Hepatitis C, Chronic / therapy
  • Humans
  • Interleukin-7 / immunology*
  • Interleukin-7 Receptor alpha Subunit / immunology*
  • Killer Cells, Natural
  • Male
  • Middle Aged
  • STAT5 Transcription Factor / immunology
  • Signal Transduction / immunology*

Substances

  • Antigens, CD
  • CD56 Antigen
  • IL7 protein, human
  • IL7R protein, human
  • Interleukin-7
  • Interleukin-7 Receptor alpha Subunit
  • NCAM1 protein, human
  • STAT5 Transcription Factor