IL-12 and IL-15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

Immun Inflamm Dis. 2018 Mar;6(1):34-46. doi: 10.1002/iid3.190. Epub 2017 Sep 27.


Introduction: Murine hepatic NK cells exhibit adaptive features, with liver-specific adhesion molecules CXCR6 and CD49a acting as surface markers.

Methods: We investigated human liver-resident CXCR6+ and CD49a+ NK cells using RNA sequencing, flow cytometry, and functional analysis. We further assessed the role of cytokines in generating NK cells with these phenotypes from the peripheral blood.

Results: Hepatic CD49a+ NK cells could be induced using cytokines and produce high quantities of IFNγ and TNFα, in contrast to hepatic CXCR6+ NK cells. RNA sequencing of liver-resident CXCR6+ NK cells confirmed a tolerant immature phenotype with reduced expression of markers associated with maturity and cytotoxicity. Liver-resident double-positive CXCR6 + CD49a+ hepatic NK cells are immature but maintain high expression of Th1 cytokines as observed for single-positive CD49a+ NK cells. We show that stimulation with activating cytokines can readily induce upregulation of both CD49a and CXCR6 on NK cells in the peripheral blood. In particular, IL-12 and IL-15 can generate CXCR6 + CD49a+ NK cells in vitro from NK cells isolated from the peripheral blood, with comparable phenotypic and functional features to liver-resident CD49a+ NK cells, including enhanced IFNγ and NKG2C expression.

Conclusion: IL-12 and IL-15 may be key for generating NK cells with a tissue-homing phenotype and strong Th1 cytokine profile in the blood, and links peripheral activation of NK cells with tissue-homing. These findings may have important therapeutic implications for immunotherapy of chronic liver disease.

Keywords: CD49a antigen; chemokine receptor 6 protein; cytokines; human liver; natural killer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chronic Disease
  • Female
  • Gene Expression Regulation / immunology*
  • Humans
  • Immune Tolerance
  • Integrin alpha1 / immunology*
  • Interleukin-12 / immunology*
  • Interleukin-15 / immunology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Liver / immunology*
  • Liver / pathology
  • Liver Diseases / immunology
  • Liver Diseases / pathology
  • Male
  • Receptors, CXCR6 / immunology*
  • Th1 Cells / immunology
  • Th1 Cells / pathology


  • CXCR6 protein, human
  • IL15 protein, human
  • Integrin alpha1
  • Interleukin-15
  • Receptors, CXCR6
  • Interleukin-12