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

Abstract

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 1 dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-a 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 1 but not Tim-3 2 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.

Trophoblast‐derived CXCL12 promotes CD56brightCD82−CD29+ NK cell enrichment in the decidua

“…39,42 Apart from trophoblast invasion and vascular remodeling, dNK cells participate in the process of decidualization and the promotion of F I G U R E 3 There is a negative correlation between CD82 and CD29 on CD56 dim dNK cells. 39,42 Apart from trophoblast invasion and vascular remodeling, dNK cells participate in the process of decidualization and the promotion of F I G U R E 3 There is a negative correlation between CD82 and CD29 on CD56 dim dNK cells.…”

“…An increasing number of studies have demonstrated the key role of dNK cells in the establishment and maintenance of maternal immunotolerance to the fetus, such as secreting Th2-type cytokines and affecting the differentiation of regulatory T (Treg) cells. 39,42 Apart from trophoblast invasion and vascular remodeling, dNK cells participate in the process of decidualization and the promotion of F I G U R E 3 There is a negative correlation between CD82 and CD29 on CD56 dim dNK cells. A, CD29 expression on dNK cells from women with normal pregnancies (n = 9) and RSA patients (n = 8) was analyzed by FCM.…”

“…39,40 The purified These methods provide CD3 − CD56 + dNK and pNK cells with a purity of more than 95%.…”

Hepatitis A virus cellular receptor 2 (HAVCR2) is decreased with viral infection and regulates pro‐labour mediators OA

“…48 Other studies have reported trophoblast cells express and secrete LGALS9, and via the LGALS9/HAVCR2 signalling pathway, can induce natural killer (NK) cells to differentiate into decidual-like NK (dNK) cells. 49 These HAVCR2 + dNK cells produce high levels of IL4 and low TNF. Therefore, it is feasible that LGALS9 could be used in the management of preterm birth by increasing HAVCR2 activation to reduce inflammation associated with labour.…”

Systemic Expression of Galectin Genes in Periparturient Goats

“…and function [14,25,26]. Previous studies conducted by our research group has reported the 74 expression off galectins in ruminants [27].…”