Human leukocyte antigen-G1 inhibits natural killer cytotoxicity through blocking the activating signal transduction pathway and formation of activating immunologic synapse.

Nonclassical major histocompatibility complex (MHC) class I molecule human leukocyte antigen (HLA)-G is normally expressed on the placental cells, especially fetal endothelial cells and invasive cytotrophoblast cells at the maternal-fetal interface. This antigen meditates immune tolerance in pregnancy through interaction with immune cells including natural killer (NK) cells. In this study, we investigated the mechanisms underlying HLA-G1-mediated inhibition of NK cytotoxicity using HLA-G1-transfected K562 cells and NK92 cells. We found that inhibition of NK cytotoxicity by HLA-G1 was associated with decreased formation of NK-target cell conjugates and defective formation of immunologic synapse, as characterized by actin depolarization and perforin immobilization in nonactive NK cells. HLA-G1 engagement induced dephosphorylation of Vav by tyrosine phosphatase-1 (SHP-1), and thus blocked the Syk-->MEK/ERK activating signaling pathway in activating NK cells. These results indicate that HLA-G1 inhibits NK cytotoxicity by blocking activating signal transduction pathway, which is required for the formation of activating immunologic synapse.