Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a+Eomes+ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a+Eomes+ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.
Copyright © 2017 Elsevier Inc. All rights reserved.

While CD95 is an apoptosis-inducing receptor and has emerged as a potential anticancer therapy target, mounting evidence shows that CD95 is also emerging as a tumor promoter by activating nonapoptotic signaling pathways. Gammaherpesviral infection is closely associated with lymphoproliferative diseases, including B cell lymphomas. The nonapoptotic function of CD95 in gammaherpesvirus-associated lymphomas is largely unknown. Here, we show that stimulation of CD95 agonist antibody drives the majority of sensitive gammaherpesvirus-transformed B cells to undergo caspase-dependent apoptosis and promotes the survival and proliferation of a subpopulation of apoptosis-resistant B cells. Surprisingly, CD95-mediated nonapoptotic signaling induced beta interferon (IFN-β) expression and correlatively inhibited B cell receptor (BCR)-mediated gammaherpesviral replication in the apoptosis-resistant lymphoma cells without influencing BCR signaling. Further analysis showed that IFN-β alone or synergizing with CD95 blocked the activation of lytic switch proteins and the gene expression of gammaherpesviruses. Our findings indicate that, independent of its apoptotic activity, CD95 signaling activity plays an important role in blocking viral replication in apoptosis-resistant, gammaherpesvirus-associated B lymphoma cells, suggesting a novel mechanism that indicates how host CD95 prototype death receptor controls the life cycle of gammaherpesviruses independent of its apoptotic activity.
Gammaherpesviruses are closely associated with lymphoid malignancies and other cancers. Viral replication and persistence strategies leading to cancer involve the activation of antiapoptotic and proliferation programs, as well as evasion of the host immune response. Here, we provide evidence that the stimulation of CD95 agonist antibody, mimicking one of the major mechanisms of cytotoxic T cell killing, inhibits B cell receptor-mediated gammaherpesviral replication in CD95 apoptosis-resistant lymphoma cells. CD95-induced type I interferon (IFN-β) contributes to the inhibition of gammaherpesviral replication. This finding sheds new light on the CD95 nonapoptotic function and provides a novel mechanism for gammaherpesviruses that helps them to escape host immune surveillance.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Tumor cell metastasis is a complex process that has been mechanistically linked to the epithelial-mesenchymal transition (EMT). The double-negative feedback loop between the microRNA-200 family and the Zeb1 transcriptional repressor is a master EMT regulator, but there is incomplete understanding of how miR-200 suppresses invasion. Our recent efforts have focused on the tumor cell-matrix interactions essential to tumor cell activation. Herein we utilized both our Kras/p53 mutant mouse model and human lung cancer cell lines to demonstrate that upon miR-200 loss integrin β1-collagen I interactions drive 3D in vitro migration/invasion and in vivo metastases. Zeb1-dependent EMT enhances tumor cell responsiveness to the ECM composition and activates FAK/Src pathway signaling by de-repression of the direct miR-200 target, CRKL. We demonstrate that CRKL serves as an adaptor molecule to facilitate focal adhesion formation, mediates outside-in signaling through Itgβ1 to drive cell invasion, and inside-out signaling that maintains tumor cell-matrix contacts required for cell invasion. Importantly, CRKL levels in pan-cancer TCGA analyses were predictive of survival and CRKL knockdown suppressed experimental metastases in vivo without affecting primary tumor growth. Our findings highlight the critical ECM-tumor cell interactions regulated by miR-200/Zeb1-dependent EMT that activate intracellular signaling pathways responsible for tumor cell invasion and metastasis.

This study aims to investigate the leukogenic effect of astragalus polysaccharide (APS), to compare its effect of increasing the numbers of mature granulocytes with that of granulocyte colony-stimulating factor (G-CSF), and to investigate the mechanism.
Rats were arbitrarily grouped into four groups (control, cyclophosphamide (CTX), CTX + APS, and CTX + G-CSF groups), and each group was then arbitrarily divided into five subgroups according to the time period since CTX infusion (0, 4, 7, 10, and 14 days). The expression of leukocyte selectin (L-selectin), its ligand, and shedding-related protease on granulocytes was analyzed. Leukocyte counts were obtained. Chemotactic capacity of polymorphonuclear leukocytes (PMNLs) was assessed.
Both APS and G-CSF restored the expression of L-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), CD11b/CD18, and ADAM17 to normal levels (P > 0.05 vs. control group on each time point), with APS eliciting a greater effect than G-CSF (P = 0.005 on day 7, P < 0.001 on day 10 and 14 for L-selectin; P = 0.038 on day 7, P = 0.001 on day 10, P < 0.001 on day 14 for PSGL-1; P < 0.001 on day 7, 10 and 14 for ADAM17; P < 0.001 on day 7, 10, and 14 for CD11b/CD18). The percentages of the bands and segmented bone marrow (BM) cells in myeloid neutrophils were higher in the CTX + APS group than in the CTX group on day 7 (P = 0.030) and reached normal levels on day 10 (P = 0.547) and 14 (P = 0.431) vs. control group. The ability of APS to increase numbers of PMNLs in peripheral blood after chemotherapy was significantly superior to that of G-CSF 7 days after chemotherapy (P = 0.029 on day 10, P = 0.006 on day 14). Moreover, APS more significantly improved the chemotactic ability of PMNLs among mature BM granulocytes and peripheral blood neutrophils after chemotherapy than did G-CSF (P < 0.001 on day 7, P = 0.001 on day 10 and P = 0.005 on day 14).
APS promoted the differentiation and chemotactic ability of BM granulocytes via the L-selectin signaling pathway.