title: Galectin-9 functionally impairs natural killer cells in humans and mice.
abstract: 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.
authors: Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, Colorado, USA.
authors: Lucy
authors: L
authors: Golden-Mason
authors: Rachel H
authors: RH
authors: McMahan
authors: Michael
authors: M
authors: Strong
authors: Richard
authors: R
authors: Reisdorph
authors: Spencer
authors: S
authors: Mahaffey
authors: Brent E
authors: BE
authors: Palmer
authors: Linling
authors: L
authors: Cheng
authors: Caroline
authors: C
authors: Kulesza
authors: Mitsuomi
authors: M
authors: Hirashima
authors: Toshiro
authors: T
authors: Niki
authors: Hugo R
authors: HR
authors: Rosen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D037161:Galectins / Q000235:genetics / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000502:physiology; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology
chemical_list: D037161:Galectins; C448908:HAVCR2 protein, human; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D019409:Interleukin-15; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D011991:Receptors, Virus; C508186:galectin 9, mouse; D018664:Interleukin-12