No abstract

Whereas the final differentiation of conventional dendritic cells (CDCs) from committed precursors occurs locally in secondary lymphoid or peripheral tissues, plasmacytoid dendritic cells (PDCs) are thought to fully develop in the bone marrow from common DC progenitors before migrating to the periphery. In our study, we define, for the first time, a subpopulation of CCR9 ؊ major histocompatibility complex class II low PDCs in murine bone marrow, which express E2-2 and are immediate precursors of CCR9 ؉ fully differentiated PDCs. However, CCR9 IntroductionAlthough plasmacytoid dendritic cells (PDCs) express markers of the "lymphoid" lineage, they can be derived from both common myeloid and common lymphoid progenitors. 1 Several elegant studies have convincingly shown that PDCs arise from common dendritic cell (DC) progenitors (or pro-DCs) in the bone marrow (BM), 2,3 which have the additional potential to generate precursor cells committed to conventional dendritic cell (CDC) development (pre-CDCs). 4,5 In contrast, common DC progenitors derived precursor cells committed exclusively to PDC development have not been described. Generation of PDCs is dependent on transcription factor E2-2, which drives the expression of other key transcription factors involved in PDC development and function (IRF8, Spi-B, IRF7) as well as PDC-specific markers (BST2 and Siglec H in murine PDCs, BDCA2 in human PDCs). 6 It has been reported that a population of Siglec-H-negative PDC-like cells in murine BM, which is only present in lymphocytic choriomeningitis virus-infected mice is capable of differentiating into CDCs during viral infection in a type I interferon (IFN)-dependent manner. 7,8 The potential of PDCs or committed PDC precursors to differentiate into other DC subpopulations in the absence of infection is unknown.It has been assumed from the available data that PDCs fully differentiate in the BM, circulate in the blood, and then enter lymphoid organs and peripheral tissues. CDCs, however, are generated from circulating committed precursors (pre-CDCs), which differentiate locally in lymphoid and peripheral tissues under the control of growth factors, such as Fms-like tyrosine kinase 3 ligand (Flt3L). 4,9 Thus, the development of CDC subpopulations is shaped by the local microenvironment allowing adaptation to tissue-specific functions. This has been shown recently for DCs in the intestinal lamina propria whose development from precursors is driven by local growth factors and the enteric microbial flora. [10][11][12] It is so far not clear whether PDCs in the intestine or in other peripheral tissues exclusively derive from fully differentiated circulating PDCs 13 or whether they can also differentiate locally from committed precursor cells under the influence of the specific tissue microenvironment.In this study, we identify an immediate PDC precursor in murine BM, which is characterized by expression of the transcription factor E2-2, PDC-specific markers (BST2, Siglec H), and production of type I IFN but lack of CCR9 and lo...

SummaryFatalities from schistosome infections arise due to granulomatous, immunemediated responses to eggs that become trapped in host tissues. Schistosome-specific immune responses are characterized by initial T helper type 1 (Th1) responses and our previous studies demonstrated that myeloid differentiation primary response gene 88 (Myd88)-deficient mice failed to initiate such responses in vivo. Paradoxically, schistosomal antigens fail to stimulate innate cells to release proinflammatory cytokines in vitro. Since Schistosoma mansoni infection is an intestinal disease, we hypothesized that commensal bacteria could act as bystander activators of the intestinal innate immune system to instigate Th1 responses. Using a broad spectrum of orally administered antibiotics and anti-mycotics we analysed schistosome-infected mice that were simultaneously depleted of gut bacteria. After depletion there was significantly less inflammation in the intestine, which was accompanied by decreased intestinal granuloma development. In contrast, liver pathology remained unaltered. In addition, schistosome-specific immune responses were skewed and faecal egg excretion was diminished. This study demonstrates that host microbiota can act as a third partner in instigating helminth-specific immune responses.

Caveolin-1 is a scaffold protein of caveolae that acts as a tumor modulator by interacting with cell adhesion molecules and signaling receptors. The role of caveolin-1 in the pathogenesis of gastric cancer (GC) is currently unknown. We show by confocal immunofluorescence microscopy and immunohistochemistry of biopsies from GC patients (n = 41) that the nonneoplastic mucosa expressed caveolin-1 in foveolar epithelial cells and adjacent connective tissue. GC cells of only 3 of 41 (7%) patients expressed caveolin-1 and were all of the intestinal type. Quantitative PCR and Western blotting confirmed that, compared with nonneoplastic tissue, the overall caveolin-1 mRNA was decreased in 14 of 19 (74%) GC patients and protein in 7 of 13 (54%), respectively. Strong caveolin-1 reactivity was found in the nonepithelial compartment (myocytes, fibroblasts, perineural, and endothelial cells) in both tumor-free and GC samples. In a series of human GC cell lines, caveolin-1 expression was low in cells derived from a primary tumor (AGS and SNU-1) but was increased in cell lines originating from distant metastases (MKN-7, MKN-45, NCI-N87, KATO-III, and SNU-5). Ectopic expression of caveolin-1 in AGS cells decreased proliferation but promoted anchorageindependent growth and survival. RNAi-mediated knockdown of endogenous caveolin-1 in MKN-45 cells accelerated cell growth. These data indicate that caveolin-1 exhibits a stagedependent differential expression and function in GC and may thereby contribute to its pathogenesis. [Cancer Res 2007;67(18):8519-26]