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

SummaryNonclassical 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.