LILRB4 regulates the function of decidual MDSCs via the SHP-2/STAT6 pathway during Toxoplasma gondii infection

Abstract

Background Toxoplasma gondii infection can cause adverse pregnancy outcomes, such as recurrent abortion, fetal growth restriction and infants with malformations, among others. Decidual myeloid-derived suppressor cells (dMDSCs) are a novel immunosuppressive cell type at the fetal-maternal interface which play an important role in sustaining normal pregnancy that is related to their high expression of the inhibitory molecule leukocyte immunoglobulin-like receptor B4 (LILRB4). It has been reported that the expression of LILRB4 is downregulated on decidual macrophages after T. gondii infection, but it remains unknown whether T. gondii infection can induce dMDSC dysfunction resulting from the change in LILRB4 expression. Methods LILRB4-deficient (LILRB4−/−) pregnant mice infected with T. gondii with associated adverse pregnancy outcomes, and anti-LILRB4 neutralized antibodies-treated infected human dMDSCs were used in vivo and in vitro experiments, respectively. The aim was to investigate the effect of LILRB4 expression on dMDSC dysfunction induced by T. gondii infection. Results Toxoplasma gondii infection was observed to reduce STAT3 phosphorylation, resulting in decreased LILRB4 expression on dMDSCs. The levels of the main functional molecules (arginase-1 [Arg-1], interleukin-10 [IL-10]) and main signaling molecules (phosphorylated Src-homology 2 domain-containing protein tyrosine phosphatase [p-SHP2], phosphorylated signal transducer and activator of transcription 6 [p-STAT6]) in dMDSCs were all significantly reduced in human and mouse dMDSCs due to the decrease of LILRB4 expression induced by T. gondii infection. SHP-2 was found to directly bind to STAT6 and STAT6 to bind to the promoter of the Arg-1 and IL-10 genes during T. gondii infection. Conclusions The downregulation of LILRB4 expression on dMDSCs induced by T. gondii infection could regulate the expression of Arg-1 and IL-10 via the SHP-2/STAT6 pathway, resulting in the dysfunction of dMDSCs, which might contribute to adverse outcomes during pregnancy by T. gondii infection. Graphical abstract

LILRB4 knockdown inhibits aortic dissection development by regulating pyroptosis and the JAK2/STAT3 signaling pathway

“…LILRB4, also known as ILT3, is an essential immune checkpoint molecule that maintains immune homeostasis and modulates immune responses. LILRB4 is associated with several diseases, including cancer, autoimmune diseases, chronic inflammation, infectious diseases, and transplantation 27 – 31 . LILRB4 is highly expressed in acute myeloid leukemia and mediates T-cell suppression and infiltration 32 .…”

Study on the mechanism of dNK cells dysfunction resulting from the IDO downregulation in dMDSCs with Toxoplasma gondii infection

“…It could cause severe pregnancy complications, such as abortion, stillbirth, anencephaly, and congenital toxoplasmosis 1,2,47 . Our previous studies reported that the abnormal pregnant outcomes with T. gondii infection were due to the dysfunction of decidual immune cells resulted from the abnormal expression of functional membrane molecules and abnormal production of cytokines in dNK cells, dMDSCs, dMφ, dDCs and dTregs 3,4,5,6,48,49 . Recently, a novel decidual MDSCs have drawn increased attention due to their outstanding immune suppressive properties, which play an important role in sustaining human pregnancy 8.9 .…”

“…Studies have proved that WT mice infected with T. gondii in early pregnancy can cause serious adverse pregnancy outcomes, which are caused by the dysfunction of immune cells, such as dMDSCs 48,49 , dNK cells 3,53 , dMφ 4,54 and dDCs 5,14 found that the depletion of dMDSCs at the maternal-fetal interface could upregulate the cytotoxicity of dNK cells, leading to pregnancy failures 29 . Human dNK cells are account for about 70% of all decidual immune cells and highly express IL-10 and TGF-β to maintain maternal-fetal immune tolerance and promote fetal development 34 .…”

LILRB4 Checkpoint for Immunotherapy: Structure, Mechanism and Disease Targets

“…LILRB4 is a central inhibitory receptor for uterine dendritic cells (uDCs) and decidual myeloid-derived suppressor cells (dMDSCs), and it plays an important immunomodulatory role at the maternal-fetal interface, thereby ensuring that the process of pregnancy proceeds normally [38,101]. HLA-G is a non-classical MHC class I molecule that is selectively and highly expressed in extrachorionic trophoblast cells invading the uterine metaphysis [102].…”