Human decidua mesenchymal stem cells regulate decidual natural killer cell function via interactions between collagen and leukocyte-associated immunoglobulin-like receptor 1

Abstract

The development of maternal tolerance to the fetal allograft in critical for the maintenance of the pregnancy, and it is accompanied by the development of a special decidual natural killer (dNK) cell tolerance phenotype. To understand the factors that influence dNK cells during early pregnancy, the present study aimed to identify mesenchymal stem cells (MSCs) from human first‑trimester deciduas, termed decidual MSCs (DMSCs), and to investigate the effect of DMSCs on the regulation of dNK cells via collagen. Decidual samples were collected from women with normal pregnancy that had undergone elective vaginal surgical terminations at 6‑9 weeks gestation. DMSCs derived from human decidual tissues were cultured under differentiation conditions to examine their multipotent differentiation capacities, and the expression of MSC‑specific markers, including cluster of differentiation (CD)44, CD73, CD105, CD90, CD34, CD31, CD14, CD45, CD11b and human leukocyte antigen‑antigen D related, was determined. dNK cells were co‑cultured with DMSCs in order to examine the effect of DMSCs on the tolerance phenotype of dNK cells. The expression of cell surface molecules, natural cytotoxicity triggering receptor 3 and killer cell immunoglobulin‑like receptor (KIR) 2DL1, and the secretion of cytokines, including interferon‑γ, tumor necrosis factor (TNF)‑α, interleukin (IL)‑10, IL‑4 and perforin, were examined by flow cytometry analysis. To determine whether the regulation of dNK cells by DMSCs was mediated by collagen, DMSCs were pre‑treated with human recombinant leukocyte‑associated immunoglobulin‑like receptor (LAIR)‑2 and transfected with pScoR‑GFP‑hP4H to inhibit the interaction between LAIR‑1 and collagen. The present results demonstrated that collagen produced by DMSCs increased the expression of KIR2DL1 and IL‑4, decrease the expression of NKp30 and TNF‑α. In conclusion, the results of the present study demonstrated that DMSCs may be cultured in vitro for prolonged periods, whilst retaining the ability to differentiate into different cell lineages. In addition, DMSCs may modulate the function of dNK cells via the interaction between collagen and LAIR‑1.

IL-27 Promotes Human Placenta–Derived Mesenchymal Stromal Cell Ability To Induce the Generation of CD4+IL-10+IFN-γ+ T Cells via the JAK/STAT Pathway in the Treatment of Experimental Graft-versus-Host Disease

“…The different results, which may be because of the different origin and culture conditions of MSCs, remain to be further studied. MSCs exert regulatory effects on various cells of the immune system, such as dendritic cells, NK cells, and T cells (41,42). Results from numerous studies and our laboratory showed that hPMSCs can induce the generation of different Treg subsets, such as CD4 + CXCR5 + Foxp3 + , CD4 + CD25 + Foxp3 + , CD8 + CD25 + Foxp3 + , CD4 + IL-10 + , and CD8 + IL-10 + Treg subsets (18).…”

Mechanisms of Key Innate Immune Cells in Early- and Late-Onset Preeclampsia

“…This may potentiate the transition of peripheral into decidual NK cells, a process critical for adequate decidual function. Decidual MSCs in addition regulate dNK through their intracellular cytokine expression profile, including TNF-α and IL-4 and via the interaction between collagen and LAIR-1 ( 171 ). Bone marrow-derived MSCs are also capable of modulating NK cells by inhibiting their proliferation, cytokine secretion, and cytotoxicity against HLA-class I- expressing targets, either via soluble factors or via cell-to-cell specific interactions ( 172 , 173 ).…”

Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress

“…Both autologous and allogeneic MSCs have been found dissolved by cytokineactivated NK cells when sufficient activating receptors expressing on NK cells [98]. Incubation of MSCs with IFN-γ partially protected them from NK-cell-mediated cytotoxicity, suggesting a microenvironment rich in IFN-γ might favor MSCs inhibiting NK cells, whereas in the absence of IFN-γ, the balance would be tilted towards NK cells eliminating MSCs [92][93][94][95][96][98][99][100]. Similarly, it has been shown that TLR4-primed MSCs were more resistant than unprimed MSCs to activated NK cell killing, and in contrast, no comparable protection was observed after TLR7/ 8-priming of MSCs [97,[101][102][103].…”

“…MSCs can be strong inhibitors of NK cells in terms of proliferation and cytotoxicity. It has been shown the presence of MSCs substantially reduced IL-2/15-induced NK cell proliferation, cytotoxicity, the production of IFN-γ, and the level of perforin and granzymes [ 93 – 95 ]. Furthermore, the expression of surface receptors, such as NKp30, NKp44, and natural-killer group 2 member D (NKG2D) typically involved in NK cell activation and target cell killing, were also downregulated.…”