EBV-associated mononucleosis does not induce long-term global deficit in T-cell responsiveness to IL-15

It has been reported that infectious mononucleosis (IM)-symptomatic primary Epstein-Barr virus infection produces a global down-regulation of interleukin-15 receptor-\u3b1 (IL-15R\u3b1) on T cells and natural killer cells associated with a defective IL-15 responsiveness that lasts for many years after the disease episode. In contrast with these results, our data indicate that, in the T-cell compartment derived from remote IM subjects, there is no quantitative or qualitative defect in the expression of the IL-15R\u3b1 chain and no deficit in T-cell responsiveness to IL-15. We observed efficient signal transduction, survival, and proliferation even in response to low IL-15 concentrations. These data are relevant and shed new light on the immune long-term response in IM subjects because they contradict the hypothesis that defects in Epstein-Barr virus-host immune balance may be correlated with a long-lasting global deficit in T-cell responsiveness to IL-15. \ua9 2009 by The American Society of Hematology

NEMO-SN1 (Western Ionian Sea, off Eastern Sicily): Example of architecture of a cabled observatory

NEMO-SN1, located in the central Mediterranean Sea, Western Ionian Sea, off Eastern Sicily Island (Southern Italy) at 2100 m water depth, 25 km from the harbour of the city of Catania, is a prototype of a cabled deep-sea multiparameter observatory and the first operating with real-time data transmission in Europe since 2005. NEMO-SN1 is also the first-established node of EMSO (European Multidisciplinary Seafloor Observatory, http://emso-eu.org), one of the incoming European large-scale research infrastructure included since 2006 in the Roadmap of the ESFRI (European Strategy Forum on Research Infrastructures, http://cordis.europa.eu/esfri/roadmap.htm), which will specifically address long-term monitoring of environmental processes related to Marine Ecosystems, Climate Change and Geo-hazards. NEMO-SN1 has been deployed and developed over the last decade thanks to Italian resources and to the EC project ESONET-NoE (European Seas Observatory NETwork - Network of Excellence, 2007-2011) that funded the LIDO-DM (Listening to the Deep Ocean - Demonstration Mission) and a technological interoperability test (http://www.esonet-emso.org/esonet-noe/). NEMO-SN1 is performing geophysical and environmental long-term monitoring by acquiring seismological, geomagnetic, gravimetric, accelerometric, physico-oceanographic, hydro-acoustic, bioacoustic measurements specifically related to earthquakes and tsunamis generation and ambient noise characterisation in term of marine mammal sounds, environmental and anthropogenic sources. A further main feature of NEMO-SN1 is to be an important test-site for the construction of KM3NeT (Kilometre-Cube Underwater Neutrino Telescope, http://www.km3net.org/), another large-scale research infrastructure included in the ESFRI Roadmap constituted by a large volume neutrino telescope. The description of the observatory and the most recent data acquired will be presented and framed in the general objectives of EMSO.PublishedTokio, 5-8 April 20114.4. Scenari e mitigazione del rischio ambientale4.6. Oceanografia operativa per la valutazione dei rischi in aree marinerestricte

NEMO-SN1 Abyssal Cabled Observatory in the Western Ionian Sea

The “NEutrino Mediterranean Observatory - Submarine Network 1” (NEMO-SN1) seafloor observatory is located in the central Mediterranean Sea, Western Ionian Sea, off Eastern Sicily (Southern Italy) at 2100 m water depth, 25 km from the harbour of the city of Catania. It is a prototype of a cabled deep-sea multiparameter observatory and the first one operating with real-time data transmission in Europe since 2005. NEMO-SN1 is also the first-established node of the “European Multidisciplinary Seafloor and water column Observatory” (EMSO, http://www.emso-eu.org), one of the incoming European large-scale research infrastructures included in the Roadmap of the “European Strategy Forum on Research Infrastructures” (ESFRI, http://cordis.europa.eu/esfri/roadmap.htm) since 2006. EMSO will specifically address long-term monitoring of environmental processes related to Marine Ecosystems, Climate Change and Geo-hazards. NEMO-SN1 has been deployed and developed over the last decade thanks to Italian funding and to the EC project “European Seas Observatory NETwork - Network of Excellence” (ESONET-NoE, 2007-2011) that funded the “Listening to the Deep Ocean - Demonstration Mission” (LIDO-DM) and a technological interoperability test (http://www.esonet-emso.org/). NEMOSN1 is performing geophysical and environmental long-term monitoring by acquiring seismological, geomagnetic, gravimetric, accelerometric, physico-oceanographic, hydroacoustic, bio-acoustic measurements. Scientific objectives include studying seismic signals, tsunami generation and warnings, its hydroacoustic precursors, and ambient noise characterisation in terms of marine mammal sounds, environmental and anthropogenic sources. NEMO-SN1 is also an important test-site for the construction of the “Kilometre-Cube Underwater Neutrino Telescope” (KM3NeT, http://www.km3net.org/), another large-scale research infrastructure included in the ESFRI Roadmap based on a large volume neutrino telescope. The description of the observatory and its most recent implementations is presented. On 9th June, 2012 NEMO-SN1 was successfully deployed and is working in real-time.Published358 - 3741.8. Osservazioni di geofisica ambientaleJCR Journalrestricte

Generation of a Novel Regulatory NK Cell Subset from Peripheral Blood CD34+ Progenitors Promoted by Membrane-Bound IL-15

BACKGROUND: NK cells have been long time considered as cytotoxic lymphocytes competent in killing virus-infected cells and tumors. However, NK cells may also play essential immuno-regulatory functions. In this context, the real existence of a defined NK subset with negative regulatory properties has been hypothesized but never clearly demonstrated. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we show the in vitro generation from human peripheral blood haematopoietic progenitors (PB-HP), of a novel subset of non-cytolytic NK cells displaying a mature phenotype and remarkable immuno-regulatory functions (NK-ireg). The main functional hallmark of these NK-ireg cells is represented by the surface expression/release of HLA-G, a major immunosuppressive molecule. In addition, NK-ireg cells secrete two powerful immuno-regulatory factors: IL-10 and IL-21. Through these factors, NK-ireg cells act as effectors of the down-regulation of the immune response: reconverting mature myeloid DC (mDC) into immature/tolerogenic DC, blocking cytolytic functions on conventional NK cells and inducing HLA-G membrane expression on PB-derived monocytes. The generation of "NK-ireg" cells is obtained, by default, in culture conditions favouring cell-to-cell contacts, and it is strictly dependent on reciprocal trans-presentation of membrane-bound IL-15 forms constitutively and selectively expressed by human CD34(+) PB-HP. Finally, a small subset of NKp46(+) HLA-G(+) IL-10(+) is detected within freshly isolated decidual NK cells, suggesting that these cells could represent an in vivo counterpart of the NK-ireg cells. CONCLUSIONS/SIGNIFICANCE: In conclusion, NK-ireg cells represent a novel truly differentiated non-cytolytic NK subset with a self-sustainable phenotype (CD56(+) CD16(+) NKp30(+) NKp44(+) NKp46(+) CD94(+) CD69(+) CCR7(+)) generated from specific pSTAT6(+) GATA3(+) precursors. NK-ireg cells could be employed to develop new immuno-suppressive strategies in autoimmune diseases, transplant rejection or graft versus host diseases. In addition, NK-ireg cells can be easily derived from peripheral blood of the patients and could constitute an autologous biotherapic tool to be used combined or in alternative to other immuno-regulatory cells

Interleukin-15 Plays a Central Role in Human Kidney Physiology and Cancer through the γc Signaling Pathway

The ability of Interleukin-15 (IL-15) to activate many immune antitumor mechanisms renders the cytokine a good candidate for the therapy of solid tumors, particularly renal cell carcinoma. Although IL-15 is being currently used in clinical trials, the function of the cytokine on kidney's components has not been extensively studied; we thus investigated the role of IL-15 on normal and tumor renal epithelial cells. Herein, we analyzed the expression and the biological functions of IL-15 in normal renal proximal tubuli (RPTEC) and in their neoplastic counterparts, the renal clear cell carcinomas (RCC). This study shows that RPTEC express a functional heterotrimeric IL-15Rαβγc complex whose stimulation with physiologic concentrations of rhIL-15 is sufficient to inhibit epithelial mesenchymal transition (EMT) commitment preserving E-cadherin expression. Indeed, IL-15 is not only a survival factor for epithelial cells, but it can also preserve the renal epithelial phenotype through the γc-signaling pathway, demonstrating that the cytokine possess a wide range of action in epithelial homeostasis. In contrast, in RCC in vitro and in vivo studies reveal a defect in the expression of γc-receptor and JAK3 associated kinase, which strongly impacts IL-15 signaling. Indeed, in the absence of the γc/JAK3 couple we demonstrate the assembly of an unprecedented functional high affinity IL-15Rαβ heterodimer, that in response to physiologic concentrations of IL-15, triggers an unbalanced signal causing the down-regulation of the tumor suppressor gene E-cadherin, favoring RCC EMT process. Remarkably, the rescue of IL-15/γc-dependent signaling (STAT5), by co-transfecting γc and JAK3 in RCC, inhibits EMT reversion. In conclusion, these data highlight the central role of IL-15 and γc-receptor signaling in renal homeostasis through the control of E-cadherin expression and preservation of epithelial phenotype both in RPTEC (up-regulation) and RCC (down-regulation)

Long-Lasting Inhibitory Effects of Fetal Liver Mesenchymal Stem Cells on T-Lymphocyte Proliferation

Human bone marrow mesenchymal stem cells (BM-MSC) are multipotent progenitor cells that have transient immunomodulatory properties on Natural Killer (NK) cells, Dendritic Cells (DC), and T cells. This study compared the use of MSC isolated from bone marrow and fetal liver (FL-MSC) to determine which displayed the most efficient immunosuppressive effects on T cell activation. Although both types of MSC exhibit similar phenotype profile, FL-MSC displays a much more extended in vitro life-span and immunomodulatory properties. When co-cultured with CD3/CD28-stimulated T cells, both BM-MSC and FL-MSC affected T cell proliferation by inhibiting their entry into the cell cycle, by inducing the down-regulation of phospho-retinoblastoma (pRb), cyclins A and D1, as well as up-regulating p27kip1expression. The T cell inhibition by MSC was not due to the soluble HLA-G5 isoform, but to the surface expression of HLA-G1, as shown by the need of cell-cell contact and by the use of neutralizing anti-HLA-G antibodies. To note, in a HLA-G-mediated fashion, MSC facilitated the expansion of a CD4low/CD8low T subset that had decreased secretion of IFN-γ, and an induced secretion of the immunomodulatory cytokine IL-10. Because of their longer lasting in vitro immunosuppressive properties, mainly mediated by HLA-G, and their more efficient induction of IL-10 production and T cell apoptosis, fetal liver MSC could be considered a new tool for MSC therapy to prevent allograft rejection

Aging Alters Functionally Human Dermal Papillary Fibroblasts but Not Reticular Fibroblasts: A New View of Skin Morphogenesis and Aging

Understanding the contribution of the dermis in skin aging is a key question, since this tissue is particularly important for skin integrity, and because its properties can affect the epidermis. Characteristics of matched pairs of dermal papillary and reticular fibroblasts (Fp and Fr) were investigated throughout aging, comparing morphology, secretion of cytokines, MMPs/TIMPs, growth potential, and interaction with epidermal keratinocytes. We observed that Fp populations were characterized by a higher proportion of small cells with low granularity and a higher growth potential than Fr populations. However, these differences became less marked with increasing age of donors. Aging was also associated with changes in the secretion activity of both Fp and Fr. Using a reconstructed skin model, we evidenced that Fp and Fr cells do not possess equivalent capacities to sustain keratinopoiesis. Comparing Fp and Fr from young donors, we noticed that dermal equivalents containing Fp were more potent to promote epidermal morphogenesis than those containing Fr. These data emphasize the complexity of dermal fibroblast biology and document the specific functional properties of Fp and Fr. Our results suggest a new model of skin aging in which marked alterations of Fp may affect the histological characteristics of skin