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Numerous patient-based studies have highlighted the protective role of immunoglobulin E-mediated allergic diseases on glioblastoma (GBM) susceptibility and prognosis. However, the mechanisms behind this observation remain elusive. Our objective was to establish a preclinical model able to recapitulate this phenomenon and investigate the role of immunity underlying such protection.An immunocompetent mouse model of allergic airway inflammation (AAI) was initiated before intracranial implantation of mouse GBM cells (GL261). RAG1-KO mice served to assess tumor growth in a model deficient for adaptive immunity. Tumor development was monitored by MRI. Microglia were isolated for functional analyses and RNA-sequencing. Peripheral as well as tumor-associated immune cells were characterized by flow cytometry. The impact of allergy-related microglial genes on patient survival was analyzed by Cox regression using publicly available datasets.We found that allergy establishment in mice delayed tumor engraftment in the brain and reduced tumor growth resulting in increased mouse survival. AAI induced a transcriptional reprogramming of microglia towards a pro-inflammatory-like state, uncovering a microglia gene signature, which correlated with limited local immunosuppression in glioma patients. AAI increased effector memory T-cells in the circulation as well as tumor-infiltrating CD4Our results demonstrate that AAI limits both tumor take and progression in mice, providing a preclinical model to study the impact of allergy on GBM susceptibility and prognosis, respectively. We identify a potentiation of local and adaptive systemic immunity, suggesting a reciprocal crosstalk that orchestrates allergy-induced immune protection against GBM.

HIV-1 persists in viral reservoirs of latently infected CD4+T cells containing integrated replication-competent viral DNA. Combined Antiretroviral Therapy (cART) does not eradicate HIV-1 reservoirs and treatment interruption will ultimately lead to viral load rebound. HIV-1 infection dramatically reduces the proportion of functional NK cell subsets and increases the expression of the checkpoint inhibitors NKG2A and KIR2DL. In this regard, we developed novel recombinant molecules combining multimers of the IL-15/IL-15Rα complex with the single-chain fragment variables (scFvs) of NKG2A or KIR2DL, and named them as Natural killer activating Multimeric immunotherapeutic compleXes (NaMiX). NaMiX significantly improved the cytotoxic activity of NK cells against HIV-1 positive ACH-2 cells and resistant Raji cancer cells by increasing their degranulation capacity, release of granzyme B, perforin and IFN-γ expression. Targeting the NKG2A receptor had a stronger effect compared to the targeting of the KIR2DL receptor due to its higher expression on NK cells. In a viral inhibition assay using CD4+T cells from HIV-1 positive patients under cART, NaMiX initially increased viral replication which was subsequently inhibited by stimulated NK cells. In humanized NSG tg-huIL-15 mice showing functional NK cells, we observed enhanced activation, degranulation and killing by NK cells from the spleen of mice treated with anti-NKG2A NaMiX compared to the cells of control mice previously infected with HIV-1 and treated with cART. Although NaMiX did not delay viral load rebound after treatment interruption in a first attempt, it tend to decrease total HIV-1 DNA in the lungs of the mice. Blocking the inhibitory receptor NKG2A in combination with targeted multimers of IL-15 on NK cells could therefore be a promising immunotherapeutic strategy towards HIV-1 functional cure.

The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF-family receptor-α2 (GFRα2) and its ligand, neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects., S.G. was supported by the NIH-OXCAM Program and the Gates Cambridge Trust. A.G.G. received fellowships from Ramón Areces and La Caixa Foundations. C.K. was supported by Marie Curie Career Integration grant H2020-MSCA-IF-2015-70841. M.S. and R.S. were supported by DFG, Se 697/7-1 and BMBF through the EnergI consortium TP6. J.V. and J.J.T.-A. were supported by Instituto de Salud Carlos III (PI12/02574), Junta de Andalucia (P12-CTS-2739), and, together with S.M.-F., by Red TerCel (ISCIII-Spanish Cell Therapy Network). S.A. and C.D.B. were supported by Versus Arthritis grant 21156. A.W.M. received funding from Versus Arthritis (21156). P.G.R. and S.G. were supported by the DIR, NIDCR, a part of the IRP, NIH, and DHHS (1ZIADE000380). K.E.S.P. acknowledges the support of the Cambridge NIHR Biomedical Research Centre. This work was supported by core support grants from MRC to the Cambridge Stem Cell Institute; National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-648765), MRC-AMED grant MR/V005421/1, and a Programme Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F. This research was funded in part by the Wellcome Trust (203151/Z/16/Z).

Food safety has considerably improved worldwide, yet infections with foodborne human enteric pathogens, such as Listeria spp. and Salmonella spp., still cause numerous hospitalizations and fatalities. Since dietary alterations, including fiber deficiency, might impact the colonization resistance mediated by the gut microbiome, studying the diet–microbiome–pathogen axis holds promise in further understanding the pathogenesis mechanisms. Using a gnotobiotic mouse model containing a 14-member synthetic human gut microbiota (14SM), we have previously shown that dietary fiber deprivation promotes proliferation of mucin-degrading bacteria, leading to a microbiome-mediated erosion of the colonic mucus barrier, which results in an increased susceptibility toward the rodent enteric pathogen Citrobacter rodentium. Here, we sought to understand how a low-fiber diet affects susceptibility to Listeria monocytogenes and Salmonella enterica serovar Typhimurium by using our 14SM gnotobiotic mouse model in BALB/c and C57BL/6 mouse backgrounds, respectively. Intriguingly, and in contrast to our results with C. rodentium, we observed that depriving mice of dietary fiber protected them from infections with both pathogens, compared to mice fed a standard chow. The microbiome delayed the overall pathogenicity compared to the onset of disease observed in germfree control mice. Nevertheless, we observed the same effect of diet on germfree mice, suggesting that the susceptibility is directly driven by the diet itself even in the absence of the gut microbiome. Our study points out an important observation, namely, that dietary fiber plays a crucial role in either the host’s susceptibility, the virulence of these pathogens, or both. It would be judicious to design and interpret future studies on this basis. IMPORTANCE The human enteric pathogens Listeria monocytogenes and Salmonella Typhimurium are employed as classical models in rodent hosts to understand the pathogenesis mechanisms of foodborne pathogens. Research in the past decade has stressed the importance of the gut microbial composition in modulating susceptibility to these pathogens. The results of our study—using gnotobiotic mice and germfree control animals—additionally suggest that the dietary fiber components can dominate the impact of enteropathogenic virulence over the pathogenicity-modulating properties of the gut microbiome. The significance of our research is that there is a need to carefully choose a certain chow when performing the enteropathogen-associated mouse experiments and to cautiously match the rodent diets when trying to replicate experiments across different laboratories. Finally, our data underscore the importance of using germfree control animals to study these pathogens, as our findings would have been prone to misinterpretation in the absence of these controls.

Despite significant progress in recent years, the therapeutic approach of the multiple different forms of human cancer often remains a challenge. Besides the well-established cancer surgery, radiotherapy and chemotherapy, immunotherapeutic strategies gain more and more attention, and some of them have already been successfully introduced into the clinic. Among these, immunotherapy based on natural killer (NK) cells is considered as one of the most promising options. In the present review, we will expose the different possibilities NK cells offer in this context, compare data about the theoretical background and mechanism(s) of action, report some results of clinical trials and identify several very recent trends. The pharmaceutical industry is quite interested in NK cell immunotherapy, which will benefit the speed of progress in the field.