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.
Yu
Yanrong
Y
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
Wang
Yun
Y
Feng
Meifu
M
D008841:Actin Cytoskeleton / Q000648:ultrastructure; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006680:HLA Antigens / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure; D020935:MAP Kinase Signaling System; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D051567:Proto-Oncogene Proteins c-vav; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6