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 CD49aEomes 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 CD49aEomes 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.

Infection with hepatitis B virus (HBV) is the most common cause of liver disease worldwide. However, because the current interferon (IFN)-based treatments have toxic side effects and marginal efficacy, improved antivirals are essential. Here we report that unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) from the HBV genome (HBV-CpG) induced robust expression of IFN-a by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 9 (TLR9)-dependent manner. We also identified inhibitory guanosine-rich ODNs in the HBV genome (HBV-ODN) that are capable of inhibiting HBV-CpG-induced IFN-a production. Furthermore, nanoparticles containing HBV-CpG, termed NP(HBV-CpG), reversed the HBV-ODN-mediated suppression of IFN-a production and also exerted a strong immunostimulatory effect on lymphocytes. Our results suggest that NP(HBV-CpG) can enhance the immune response to hepatitis B surface antigen (HBsAg) and skew this response toward the Th1 pathway in mice immunized with rHBsAg and NP(HBV-CpG). Moreover, NP(HBV-CpG)-based therapy led to the efficient clearance of HBV and induced an anti-HBsAg response in HBV carrier mice. Conclusion: Endogenous HBV-CpG ODNs from the HBV genome induce IFN-a production so that nanoparticle-encapsulated HBV-CpG may act as an HBsAg vaccine adjuvant and may also represent a potent therapeutic agent for the treatment of chronic HBV infection. (HEPATOLOGY 2014;59:385-394) P ersistent infection with the hepatitis B virus (HBV) affects more than 360 million people worldwide and has become a severe public health problem owing to the increased risk of liver cirrhosis and hepatocellular carcinoma in infected individuals. The current recombinant hepatitis B surface antigen (rHBsAg) vaccine provides protection against HBV infection but fails to protect 10% of those who are vaccinated and is also ineffective for individuals who are already infected with HBV. Conventional antiviral drugs used for the treatment of HBV, including lamivudine and interferon-alpha (IFN-a), suppress viral replication and reduce hepatic symptoms. 1 However, the persistence of HBV covalently closed circular DNA (cccDNA) and defective immune responses lead to treatment failure and progression to liver disease. 2 Therefore, more efficient therapeutic strategies are needed to eradicate HBV infection.HBV seems to avoid inducing strong innate immune responses including the type I IFN response. 2 Therefore, methods of inducing vigorous immune responses against HBV may play a critical role in the clearance of HBV infection. The unmethylated cytosine-phosphate-guanosine (CpG) motifs presented in bacterial DNA can stimulate the immune system by interacting with the pattern-recognition receptor Tolllike receptor 9 (TLR9). 3 TLR9 is predominantly expressed in plasmacytoid dendritic cells (pDCs) and

The epithelium of the intestine functions as the primary “frontline” physical barrier for protection from enteric microbiota. Intraepithelial lymphocytes (IELs) distributed along the intestinal epithelium are predominantly CD8+ T cells, among which CD8αβ+ IELs are a large population. In this investigation, the proportion and absolute number of CD8αβ+ IELs decreased significantly in antibiotic-treated and germ-free mice. Moreover, the number of CD8αβ+ IELs was correlated closely with the load of commensal microbes, and induced by specific members of commensal bacteria. Microarray analysis revealed that CD8αβ+ IELs expressed a series of genes encoding potent antimicrobial peptides (AMPs), whereas CD8αβ+ splenocytes did not. The antimicrobial activity of CD8αβ+ IELs was confirmed by an antimicrobial-activity assay. In conclusion, microbicidal CD8αβ+ IELs are regulated by commensal bacteria which, in turn, secrete AMPs that have a vital role in maintaining the homeostasis of the small intestine.

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