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NK cell reactivity is dynamically regulated by IL-15, and NK cells do not need more than a few minutes of exposure to remember the cytokine for several hours., IL-15 priming of NK cells is a broadly accepted concept, but the dynamics and underlying molecular mechanisms remain poorly understood. We show that as little as 5 min of IL-15 treatment in vitro, followed by removal of excess cytokines, results in a long-lasting, but reversible, augmentation of NK cell responsiveness upon activating receptor cross-linking. In contrast to long-term stimulation, improved NK cell function after short-term IL-15 priming was not associated with enhanced metabolism but was based on the increased steady-state phosphorylation level of signalling molecules downstream of activating receptors. Inhibition of JAK3 eliminated this priming effect, suggesting a cross talk between the IL-15 receptor and ITAM-dependent activating receptors. Increased signalling molecule phosphorylation levels, calcium flux, and IFN-γ secretion lasted for up to 3 h after IL-15 stimulation before returning to baseline. We conclude that IL-15 rapidly and reversibly primes NK cell function by modulating activating receptor signalling. Our findings suggest a mechanism by which NK cell reactivity can potentially be maintained in vivo based on only brief encounters with IL-15 trans-presenting cells.

Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g., tumor or virus-infected cells. A desired property of cancer immunotherapy is, therefore, to activate educated NK cells during anti-tumor responses in vivo. We here analyze NK cell responses to &alpha, galactosylceramide (&alpha, GC), a potent activator of invariant NKT (iNKT) cells, or to exosomes loaded with &alpha, GC. In mouse strains which express different MHC-I alleles using an extended NK cell flow cytometry panel, we show that &alpha, GC induces a biased NK cell proliferation of educated NK cells. Importantly, iNKT cell-induced activation of NK cells selectively increased in vivo missing self-responses, leading to more effective rejection of tumor cells. Exosomes from antigen-presenting cells are attractive anti-cancer therapy tools as they may induce both innate and adaptive immune responses, thereby addressing the hurdle of tumor heterogeneity. Adding &alpha, GC to antigen-loaded dendritic-cell-derived exosomes also led to an increase in missing self-responses in addition to boosted T and B cell responses. This study manifests &alpha, GC as an attractive adjuvant in cancer immunotherapy, as it increases the functional capacity of educated NK cells and enhances the innate, missing self-based antitumor response.

International audience; The aim of the GER-e-TEC™ project is to study the contribution of telemonitoring residents in nursing homes of Rouen University Hospital, with astructuring and recording of medical care in order to avoid situations of acute decompensation and complication of geriatric risks.E-care platform will provide personalized care for the main geriatric risks, to avoid the occurrence of an acute decompensation factor in the elderly patient. The collection of information by the platform will increase knowledge of the patients and provide a particularly effective tool for transmission between nursing staff and general practitioners in nursing homes. This information collection will allow the extraction of markers to improve the early detection of any decompensation and thus improve patient monitoring and reduce the number of hospitalizations. The platform will also provide any paramedical and medical health professional with the resident's geriatric data, which will be updated regularly, including the anthropometric, nutritional, cognitive and iatrogenic data, constituting a real illustration integrated into the electronic platform of the standardized gerontological evaluation, thanks to simple and non-time-consuming measures. Geriatric

Elderly and very elderly people living in nursing homes are frequently being hospitalized, more often than not in emergency situations, and the number is steadily increasing.

Natural killer T (NKT) cells recognize glycolipids presented on CD1d. They share features of adaptive T lymphocytes and innate NK cells, and mediate immunoregulatory functions via rapid production of cytokines. Invariant (iNKT) and diverse (dNKT) NKT cell subsets are defined by their TCR. The immunological role of dNKT cells, that do not express the invariant TCRα-chain used by iNKT cells, is less well explored than that of iNKT cells. Here, we investigated signals driving Toll-like receptor (TLR) ligand activation of TCR-transgenic murine dNKT cells. IFN-γ production by dNKT cells required dendritic cells (DC), cell-to-cell contact and presence of TLR ligands. TLR-stimulated DC activated dNKT cells to secrete IFN-γ in a CD1d-, CD80/86- and type I IFN-independent manner. In contrast, a requirement for IL-12p40, and a TLR ligand-selective dependence on IL-18 or IL-15 was observed. TLR ligand/DC stimulation provoked early secretion of pro-inflammatory cytokines by both CD62L+ and CD62L− dNKT cells. However, proliferation was limited. In contrast, TCR/co-receptor-mediated activation resulted in proliferation and delayed production of a broader cytokine spectrum preferentially in CD62L− dNKT cells. Thus, innate (TLR ligand/DC) and adaptive (TCR/co-receptor) stimulation of dNKT cells resulted in distinct cellular responses that may contribute differently to the formation of immune memory.

Mesenchymal stromal cells (MSCs) exert broad immunosuppressive potential, modulating the activity of cells of innate and adaptive immune systems. As MSCs become accepted as a therapeutic option for the treatment of immunological disorders such as Graft versus Host Disease, our need to understand the intricate details by which they exert their effects is crucial. Programmed death‐1 (PD‐1) is an important regulator in T cell activation and homeostatic control. It has been reported that this pathway may be important in contact‐dependent mediated immunomodulation by MSCs. The aim of this study was to establish whether MSCs, in addition to their cell‐surface expression, are able to secrete PD‐1 ligands (PD‐L1 and PD‐L2) and their potential importance in modulating contact‐independent mechanisms of MSC immunosuppression. Here we report that MSCs express and secrete PD‐L1 and PD‐L2 and that this is regulated by exposure to interferon γ and tumor necrosis factor α. MSCs, via their secretion of PD‐1 ligands, suppress the activation of CD4+ T cells, downregulate interleukin‐2 secretion and induce irreversible hyporesponsiveness and cell death. Suppressed T cells demonstrated a reduction in AKT phosphorylation at T308 and a subsequent increase in FOXO3 expression that could be reversed with blockade of PD‐L1. In conclusion, we demonstrate for the first time, that MSCs are able to secrete PD‐1 ligands, with this being the first known report of a biological role for PD‐L2 in MSCs. These soluble factors play an important role in modulating immunosuppressive effects of MSCs directly on T cell behavior and induction of peripheral tolerance. Stem Cells 2017;35:766–776

We present the European project CAREGIVERSPRO-MMD which aims to develop a digital platform to support people with neurocognitive disorders and their carers by providing them with educational and informative content adapted to the disease and the role of carer, discussion spaces, cognitive stimulation games, a news feed, an agenda and local information (events, social structures, places of information and support...).