Galectin-9 functionally impairs natural killer cells in humans and mice

J Virol. 2013 May;87(9):4835-45. doi: 10.1128/JVI.01085-12. Epub 2013 Feb 13.


Galectin-9 is a pleiotropic immune modulator affecting numerous cell types of innate and adaptive immunity. Patients with chronic infection with either hepatitis C virus (HCV) or HIV have elevated circulating levels. Limited data exist on the regulation of natural killer (NK) cell function through interaction with galectin-9. We found that galectin-9 ligation downregulates multiple immune-activating genes, including eight involved in the NK cell-mediated cytotoxicity pathway, impairs lymphokine-activated killing, and decreases the proportion of gamma interferon (IFN-γ)-producing NK cells that had been stimulated with interleukin-12 (IL-12)/IL-15. We demonstrate that the transcriptional and functional changes induced by galectin-9 are independent of Tim-3. Consistent with these results for humans, we find that the genetic absence of galectin-9 in mice is associated with greater IFN-γ production by NK cells and enhanced degranulation. We also show that in the setting of a short-term (4-day) murine cytomegalovirus infection, terminally differentiated NKs accumulate in the livers of galectin-9 knockout mice, and that hepatic NKs spontaneously produce significantly more IFN-γ in this setting. Taken together, our results indicate that galectin-9 engagement impairs the function of NK cells, including cytotoxicity and cytokine production.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytotoxicity, Immunologic
  • Galectins / genetics
  • Galectins / immunology*
  • Hepatitis A Virus Cellular Receptor 2
  • Herpesviridae Infections / genetics
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / virology
  • Humans
  • Interleukin-12 / immunology
  • Interleukin-15 / immunology
  • Killer Cells, Natural / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / physiology
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology


  • Galectins
  • HAVCR2 protein, human
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Interleukin-15
  • LGALS9 protein, human
  • Membrane Proteins
  • Receptors, Virus
  • galectin 9, mouse
  • Interleukin-12