Decidualization-derived cAMP regulates phenotypic and functional conversion of decidual NK cells from CD56dimCD16− NK cells

In early pregnancy,the decidua is populated by a large number of natural killer cells(NKs),most of which are CD56bright with a strong capacity to secrete cytokines,differing from peripheral and cord blood NK cells(pNKs and cNKs).1,2,3 It is generally believed that uterine NKs are recruited from the peripheral blood and are further educated to develop a decidual NK cell(dNK)-like phenotype in the microenvironment at the maternal-fetal interface.4 However,the defined mechanisms involved in this education remain unclear.

Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models

Mesenchymal stem cells(MSCs),which are pluripotent cells with immunomodulatory properties,have been considered good candidates for the therapy of several immune disorders,such as inflammatory bowel diseases,concanavalin A-induced liver injury,and graft-versus-host disease.The embryo is a natural allograft to the maternal immune system.A successful pregnancy depends on the timely extinction of the inflammatory response induced by embryo implantation,followed by the switch to a tolerant immune microenvironment in both the uterus and the system.Excessive infiltration of immune cells and serious inflammatory responses are triggers for embryo rejection,which results in miscarriage.Here,we demonstrated that adoptive transfer of MSCs could prevent fetal loss in a lipopolysaccharide(LPS)-induced abortion model and immune response-mediated spontaneous abortion model.The immunosuppressive MSCs alleviated excessive inflammation by inhibiting CD4+T cell proliferation and promoting the decidual macrophage switch to M2 in a tumor necrosis factor-stimulated gene-6(TSG-6)-dependent manner.Cell-tocell contact with proinflammatory macrophages increased the TSG-6 production by the MSCs,thereby enhancing the suppressive regulation of T cells and macrophages.Moreover,proinflammatory macrophages in contact with the MSCs upregulated the expression of CD200 on the stem cells and facilitated the reprogramming of macrophages towards an anti-inflammatory skew through the interaction of CD200 with CD200R on proinflammatory macrophages.Therefore,the results demonstrate that a TSG-6-mediated paracrine effect,reinforced by cell-to-cell contact between MSCs and proinflammatory macrophages,is involved in the mechanism of MSC-mediated abortion relief through the induction of immune tolerance.Our study also indicates the potential application of MSCs in clinical recurrent miscarriages.

TIM-3: a crucial regulator of NK cells in pregnancy

In pregnancy,the maternal immune system(including innate and adaptive immunity)makes elaborate adjustments to endure the embryo’s expression of paternal antigens and to protect the embryo from attacks by invading pathogens such as bacteria or viruses.1 As the predominant innate immune cells during gestation,natural killer(NK)cells have been proven to mediate the establishment of maternal-fetal immune tolerance and to initiate appropriate defenses against infections.2 Tim-3,a member of the T-cell immunoglobulin and mucin domain proteins,has emerged as a key molecule in both innate and adaptive responses and represents a promising novel therapeutic target.