Differential T Cell Function and Fate in Lymph Node and Nonlymphoid Tissues

The functions and fate of antigen-experienced T cells isolated from lymph node or nonlymphoid tissues were analyzed in a system involving adoptive transfer of in vitro–activated T cells into mice. Activated T cells present in the lymph nodes could be stimulated by antigen to divide, produce effector cytokines, and migrate to peripheral tissues. By contrast, activated T cells that had migrated into nonlymphoid tissues (lung and airway) produced substantial effector cytokines upon antigen challenge, but were completely unable to divide or migrate back to the lymph nodes. Therefore, activated T cells can undergo clonal expansion in the lymph node, but are recruited and retained as nondividing cells in nonlymphoid tissues. These distinct regulatory events in lymph node and nonlymphoid tissues reveal simple key mechanisms for both inducing and limiting T cell immunity

The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β

It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T cell-dependent (TD) or -independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-beta or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-beta signaling inhibitor or neutralizing anti-TGF-beta was added, demonstrating the involvement of RA and TGF-beta in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant

Development of severe colitis is associated with lung inflammation and pathology

Inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis are chronic relapsing diseases that affect the gastrointestinal tract, most commonly the colon. A link between the gut and the lung is suggested since patients with IBD have an increased susceptibility for chronic inflammatory lung disease. Furthermore, in the absence of overt lung disease, IBD patients have worsened lung function and more leukocytes in sputum than healthy individuals, highlighting a conduit between the gut and lung in disease. To study the gut-lung axis in the context of IBD, we used TCRδ-/- mice, which are highly susceptible to dextran sulfate sodium (DSS) due to the importance of γδ T cells in maintenance of barrier integrity. After induction of experimental colitis using DSS, the lungs of TCRδ-/- mice exhibited signs of inflammation and mild emphysema, which was not observed in DSS-treated C57BL/6 mice. Damage to the lung tissue was accompanied by a large expansion of neutrophils in the lung parenchyma and an increase in alveolar macrophages in the lung wash. Gene expression analyses showed a significant increase in Csf3, Cxcl2, Tnfa, and Il17a in lung tissue in keeping with neutrophil infiltration. Expression of genes encoding reactive oxygen species enzymes and elastolytic enzymes were enhanced in the lungs of both C57BL/6 and TCRδ-/- mice with colitis. Similarly, surfactant gene expression was also enhanced, which may represent a protective mechanism. These data demonstrate that severe colitis in a susceptible genetic background is sufficient to induce lung inflammation and tissue damage, providing the research community with an important tool for the development of novel therapeutics aimed at reducing co-morbidities in IBD patients

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

We thank Manuel Kulagin for technical help, Pierre Bonnaventure for portal vein blood sampling, Francisco Sepulveda for technical assistance in GS-MS acquisition, and Dorothee Hahne (Metabolomics Australia, University of Western Australia) for human samples SCFA isolation, acquisition, and analysis. We also thank Cristina Cartoni (Phenotyping Unit, EPFL) for Milliplex analysis, Jessica Dessimoz and her team from the Histology Core Facility (EPFL), Miguel Garcia and his team from the Flow Cytometry Core Facility (EPFL), and staff from the EPFL CPG animal house for excellent animal care. The computations were partially performed at the Vital-IT Center for high-performance computing of the SIB Swiss Institute of Bioinformatics (http://www.vital-it.ch). The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 310948. Funding for A.W.W. and a subset of the 16S rRNA gene sequencing was provided by the Wellcome Trust (grant number WT 098051). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Predicting Responses of Geo-ecological Carbonate Reef Systems to Climate Change: A Conceptual Model and Review

Coral reefs provide critical ecological and geomorphic (e.g. sediment production for reef-fronted shoreline maintenance) services, which interact in complex and dynamic ways. These services are under threat from climate change, requiring dynamic modelling approaches that predict how reef systems will respond to different future climate scenarios. Carbonate budgets, which estimate net reef calcium carbonate production, provide a comprehensive ‘snap-shot’ assessment of reef accretionary potential and reef stability. These budgets, however, were not intended to account for the full suite of processes that maintain coral reef services or to provide predictive capacity on longer timescales (decadal to centennial). To respond to the dual challenges of enhancing carbonate budget assessments and advancing their predictive capacity, we applied a novel model elicitation and review method to create a qualitative geo-ecological carbonate reef system model that links geomorphic, ecological and physical processes. Our approach conceptualizes relationships between net carbonate production, sediment transport and landform stability, and rates knowledge confidence to reveal major knowledge gaps and critical future research pathways. The model provides a blueprint for future coral reef research that aims to quantify net carbonate production and sediment dynamics, improving our capacity to predict responses of reefs and reef-fronted shorelines to future climate change

A Transient Sub-Eddington Black Hole X-ray Binary Candidate in the Dust Lanes of Centaurus A

We report the discovery of a bright X-ray transient, CXOU J132527.6-430023, in the nearby early-type galaxy NGC 5128. The source was first detected over the course of five Chandra observations in 2007, reaching an unabsorbed outburst luminosity of 1-2*10^38 erg/s in the 0.5-7.0 keV band before returning to quiescence. Such luminosities are possible for both stellar-mass black hole and neutron star X-ray binary transients. Here, we attempt to characterize the nature of the compact object. No counterpart has been detected in the optical or radio sky, but the proximity of the source to the dust lanes allows for the possibility of an obscured companion. The brightness of the source after a >100 fold increase in X-ray flux makes it either the first confirmed transient non-ULX black hole system in outburst to be subject to detailed spectral modeling outside the Local Group, or a bright (>10^38 erg/s) transient neutron star X-ray binary, which are very rare. Such a large increase in flux would appear to lend weight to the view that this is a black hole transient. X-ray spectral fitting of an absorbed power law yielded unphysical photon indices, while the parameters of the best-fit absorbed disc blackbody model are typical of an accreting ~10 Msol black hole in the thermally dominant state.Comment: 8 pages, 6 figures, accepted for publication in Ap

Antibodies and IL-3 support helminth-induced basophil expansion

Basophils are powerful mediators of Th2 immunity and are present in increased numbers during allergic inflammation and helminth infection. Despite their ability to potentiate Th2 immunity the mechanisms regulating basophil development remain largely unknown. We have found a unique role for isotype-switched antibodies in promoting helminth-induced basophil production following infection of mice with Heligmosomoides polygyrus bakeri or Nippostrongylus brasiliensis. H. polygyrus bakeri-induced basophil expansion was found to occur within the bone marrow, and to a lesser extent the spleen, and was IL-3 dependent. IL-3 was largely produced by CD4+CD49b+NK1.1− effector T cells at these sites, and required the IL-4Rα chain. However, antibody-deficient mice exhibited defective basophil mobilization despite intact T-cell IL-3 production, and supplementation of mice with immune serum could promote basophilia independently of required IL-4Rα signaling. Helminth-induced eosinophilia was not affected by the deficiency in isotype-switched antibodies, suggesting a direct effect on basophils rather than through priming of Th2 responses. Although normal type 2 immunity occurred in the basopenic mice following primary infection with H. polygyrus bakeri, parasite rejection following challenge infection was impaired. These data reveal a role for isotype-switched antibodies in promoting basophil expansion and effector function following helminth infection

Film-Forming Systems for the Delivery of DNDI-0690 to Treat Cutaneous Leishmaniasis.

In cutaneous leishmaniasis (CL), parasites reside in the dermis, creating an opportunity for local drug administration potentially reducing adverse effects and improving treatment adherence compared to current therapies. Polymeric film-forming systems (FFSs) are directly applied to the skin and form a thin film as the solvent evaporates. In contrast to conventional topical dosage forms, FFSs strongly adhere to the skin, favouring sustained drug delivery to the affected site, reducing the need for frequent applications, and enhancing patient compliance. This study reports the first investigation of the use of film-forming systems for the delivery of DNDI-0690, a nitroimidazole compound with potent activity against CL-causing Leishmania species. A total of seven polymers with or without plasticiser were evaluated for drying time, stickiness, film-flexibility, and cosmetic attributes; three FFSs yielded a positive evaluation for all test parameters. The impact of each of these FFSs on the permeation of the model skin permeant hydrocortisone (hydrocortisone, 1% (w/v) across the Strat-M membrane was evaluated, and the formulations resulting in the highest and lowest permeation flux (Klucel LF with triethyl citrate and Eudragit RS with dibutyl sebacate, respectively) were selected as the FFS vehicle for DNDI-0690. The release and skin distribution of the drug upon application to Leishmania-infected and uninfected BALB/c mouse skin were examined using Franz diffusion cells followed by an evaluation of the efficacy of both DNDI-0690 FFSs (1% (w/v)) in an experimental CL model. Whereas the Eudragit film resulted in a higher permeation of DNDI-0690, the Klucel film was able to deposit four times more drug into the skin, where the parasite resides. Of the FFSs formulations, only the Eudragit system resulted in a reduced parasite load, but not reduced lesion size, when compared to the vehicle only control. Whereas drug delivery into the skin was successfully modulated using different FFS systems, the FFS systems selected were not effective for the topical application of DNDI-0690. The convenience and aesthetic of FFS systems alongside their ability to modulate drug delivery to and into the skin merit further investigation using other promising antileishmanial drugs