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

Area of Science:

• Immunology
• Cell Biology

Background:

• Galectin-9 is an immune modulator with elevated levels in chronic Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) infections.
• Limited information exists regarding galectin-9's specific effects on natural killer (NK) cell function.

Purpose of the Study:

• To investigate the impact of galectin-9 on NK cell function, including cytotoxicity and cytokine production.
• To determine if galectin-9's effects on NK cells are mediated through Tim-3.

Main Methods:

• Investigated galectin-9 ligation effects on human NK cell gene expression and function.
• Assessed NK cell-mediated cytotoxicity and gamma interferon (IFN-γ) production.
• Utilized galectin-9 knockout mice to study NK cell responses in vivo during murine cytomegalovirus (MCMV) infection.

Main Results:

• Galectin-9 ligation downregulated immune-activating genes in NK cells, including those in the cytotoxicity pathway.
• Impaired lymphokine-activated killing and reduced IFN-γ production by IL-12/IL-15-stimulated NK cells were observed.
• Galectin-9 knockout mice showed increased NK cell IFN-γ production and degranulation, with enhanced hepatic NK cell activity during MCMV infection.
• Galectin-9's effects on NK cells were independent of Tim-3.

Conclusions:

• Galectin-9 engagement impairs critical NK cell functions, including cytotoxicity and cytokine production.
• These findings highlight galectin-9 as a negative regulator of NK cell activity, relevant in chronic viral infections.