Synthesis, Crystal Structures, and Ion Pairing of κ6N^6N Complexes with Rare‐Earth Elements in the Solid State and in Solution

The rare earth element complexes (Ln=Y, La, Sm, Lu, Ce) of several podant κ$^6N$-coordinating ligands have been synthetized and thoroughly characterized. The structural properties of the complexes have been investigated by X-ray diffraction in the solid state and by advanced NMR methods in solution. To estimate the donor capabilities of the presented ligands, an experimental comparison study has been conducted by cyclic voltammetry as well as absorption experiments using the cerium complexes and by analyzing $^{89}$Y NMR chemical shifts of the different yttrium complexes. In order to obtain a complete and detailed picture, all experiments were corroborated by state-of-the-art quantum chemical calculations. Finally, coordination competition studies have been carried out by means of $^1$H and $^{31}$P NMR spectroscopy to investigate the correlation with donor properties and selectivity

Juvenile Greylag Geese (Anser anser) Discriminate between Individual Siblings

Social species that maintain individualised relationships with certain others despite continuous changes in age, reproductive status and dominance rank between group members ought to be capable of individual recognition. Tests of “true” individual recognition, where an individual recognises unique features of another, are rare, however. Often kinship and/or familiarity suffice to explain dyadic interactions. The complex relationships within a greylag goose flock suggest that they should be able to recognise individuals irrespective of familiarity or kinship. We tested whether six-week-old hand-raised greylags can discriminate between two of their siblings. We developed a new experimental protocol, in which geese were trained to associate social siblings with geometrical symbols. Subsequently, focals were presented with two geometrical symbols in the presence of a sibling associated with one of the symbols. Significant choice of the geometrical symbol associated with the target present indicated that focals were able to distinguish between individual targets. Greylag goslings successfully learned this association-discrimination task, regardless of genetic relatedness or sex of the sibling targets. Social relationships within a goose flock thus may indeed be based on recognition of unique features of individual conspecifics

A Notch/STAT3-driven Blimp-1/c-Maf-dependent molecular switch induces IL-10 expression in human CD4(+) T cells and is defective in Crohn's disease patients

Immunosuppressive Interleukin (IL)-10 production by pro-inflammatory CD4(+) T cells is a central self-regulatory function to limit aberrant inflammation. Still, the molecular mediators controlling IL-10 expression in human CD4(+) T cells are largely undefined. Here, we identify a Notch/STAT3 signaling-module as a universal molecular switch to induce IL-10 expression across human naïve and major effector CD4(+) T cell subsets. IL-10 induction was transient, jointly controlled by the transcription factors Blimp-1/c-Maf and accompanied by upregulation of several co-inhibitory receptors, including LAG-3, CD49b, PD-1, TIM-3 and TIGIT. Consistent with a protective role of IL-10 in inflammatory bowel diseases (IBD), effector CD4(+) T cells from Crohn's disease patients were defective in Notch/STAT3-induced IL-10 production and skewed towards an inflammatory Th1/17 cell phenotype. Collectively, our data identify a Notch/STAT3-Blimp-1/c-Maf axis as a common anti-inflammatory pathway in human CD4(+) T cells, which is defective in IBD and thus may represent an attractive therapeutic target

Lipopolysaccharide injection induces relapses of experimental autoimmune encephalomyelitis in nontransgenic mice via bystander activation of autoreactive CD4+ cells

Infections sometimes associate with exacerbations of autoimmune diseases through pathways that are poorly understood. Ag-specific mechanisms such as cross-reactivity between a microbial Ag and a self-Ag have received no direct support. In this study, we show that injection of LPS induces experimental autoimmune encephalomyelitis in TCR-transgenic mice and relapse of encephalomyelitis in normal mice. This form of treatment induces proliferation and cytokine production in a fraction of effector/memory Th lymphocytes in vitro via physical contact of Th cells with CD4(-) LPS-responsive cells. TCR-mediated signals are not necessary; rather what is required is ligation of costimulatory receptors on Th cells by costimulatory molecules on the CD4(-) cells. This form of bystander activation provides an Ag-independent link between infection and autoimmunity that might fit the clinical and epidemiological data on the connection between infection and autoimmunity better than the Ag-specific models

Notch regulates IL-10 production by T helper 1 cells

T helper 1 (Th1) cells mediate powerful cellular immune responses. However, if unbalanced, Th1 immunity eventually may cause pathology. Recently, it has been shown that IL-10, an antiinflammatory cytokine strongly antagonizing Th1-mediated effects, can be produced by Th1 cells and is indeed essential for self-regulation of Th1 immunity. Here, we show that Notch induces IL-10 production in newly developing and already established Th1 cells via a signal transducer and activator of transcription 4 (STAT4)-dependent process. Notch signaling in the presence of the cytokines IL-12 or IL-27 induces Th1 cells to produce large amounts of IL-10 without diminishing IFN-γ production. Notch-modified Th1 cells completely lose their inflammatory capacity and instead are able to actively suppress a Th1 cell-induced delayed-type hypersensitivity (DTH) reaction in an IL-10-dependent fashion. IL-10 production can be elicited by active forms of all four mammalian Notch receptors but was found to be specific for the Delta-like family of Notch ligands. Dendritic cells (DC) selectively acquire Delta-like 4 expression upon stimulation with various Toll-like receptor (TLR) ligands and concomitantly induce IL-10 production by Th1 cells in vitro and in vivo. This effect can be selectively reversed by pharmacological inhibitors of Notch signaling (γ-secretase inhibitor). Our data suggest that Notch regulates IL-10 production in Th1 cells by a STAT4-dependent process that converts proinflammatory Th1 cells into T cells with regulatory activity. This pathway may provide unique opportunities for therapeutic intervention in Th1-driven immune diseases and for Th1-associated vaccination strategies

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human antifungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases