Inhibition of the activating signals in NK92 cells by recombinant GST-sHLA-G1α chain

Abstract

The soluble HLA-G1 (sHLA-G1) isoform was found to be secreted by trophoblast cells at the materno-fetal interface, which suggests that it may act as an immunomodulator during pregnancy. In this paper, we reported that GST-sHLA-G1α chain could bind to its receptor ILT-2 on NK92 cells and then the latter recruited Src homology 2 domaincontaining tyrosine phosphatase-1 (SHP-1), which consequently dephosphorylated some important protein tyrosine kinases and blocked the activation of downstream molecules such as MEK and ERK so that the cytotoxicity of natural killer (NK) cells was inhibited. These results indicated that GST-sHLA-G1α chain might be exploited in new immunotherapy strategies aiming at inducing immunotolerance during allograft, xenograft and autoimmune situations. In addition, we found that modification of O-linked β-N-acetylglucosamine (O-GlcNAc) was involved in NK cells' activating and inhibitory signals. This may provide a novel molecular target for inducing immunotolerance but needs further study.

Inhibition of human Vγ9Vδ2 T-cell antitumoral activity through HLA-G: implications for immunotherapy of cancer

“…In addition, soluble HLA-G either alone or produced by tumor cells is able to impair NK cell cytolytic activity [55][56][57][58]. Consistent with these findings, we found that M8 tumor cells expressing soluble HLA-G5 isoform were able to inhibit the cytolytic activity of Vc9Vd2 T cells as effectively as M8-HLA-G1 tumor cells (data not shown).…”

Down-regulation of HLA-G boosted natural killer cell-mediated cytolysis in JEG-3 cells cultured in vitro

“…Expression of HLA-G Is Down-Regulated by Targeting siRNA After 48 hours of infection by the recombinant adenovirus containing HLA-G siRNA, HLA-G mRNAs and proteins were isolated from [1] untransfected cells, [2] scrambled siRNA transfected cells, and [3] HLA-G siRNA transfected cells, and were analyzed by RT-PCR and Western blot. The forward and reverse primers used for RT-PCR analysis were specific to exons 5 and 6, respectively, spanning the HLA-G targeting sequences (labeled as P1 and P2 in Fig.…”

“…1B). Possible explanations for the variance between HLA-G mRNA and protein expression (76.2% vs. 51.57%) in the siRNA-treated cells include [1] that the mRNAs and proteins of different isoforms may be of different abundance, [2] that the antibody used in the present study might not have an equal ability to recognize each isoform, and [3] that steady-state levels of mRNA are not always a good forecaster of steady-state levels of the corresponding protein.…”

“…Functions of HLA-G include inhibition of [1] allogenic proliferation of T cells, [2] NK cell cytotoxicity, [3] antigen-specific T-cell cytotoxicity, and [4] induction of apoptosis by activated CD8 þ T cells and NK cells. In addition to its immunoprotecting role, HLA-G may play a role in remodeling of spiral arteries and establishment of a hemochorial placenta (18)(19)(20).…”

“…However, maternal NK cells tolerate fetal trophoblasts that are almost devoid of MHC-Ia and MHC-II antigens. It has been confirmed that HLA-G proteins are capable of inhibiting the function of NK cells (1)(2)(3)(4)(5). However, the influence of adding HLA-G proteins on HLA-G or other upstream or downstream gene expression in target cells is not known.…”