The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy

Decidual natural killer (dNK) cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against Infection. However, how dNK cells maintain the immune balance between tolerance and Anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and Mucin domain-containing molecule-3 (TIM-3) are expressed on over 60% of dNK cells. TIM-3(+) dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of Galectin-9 (Gal-9) and the interaction between Gal-9 and TIM-3. In addition, trophoblasts inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by TIM-3 neutralizing Antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper (Th)2-type cytokines were decreased and Th1-type cytokines were increased in TIM-3(+) but not TIM-3(-) dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/TIM-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.