Summary Intact interkeulin-10 receptor (IL-10R) signaling on effector and regulatory T (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type CD4+ T cell transfer, Rag2−/−Il10rb−/− mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone marrow-derived macrophages, and their ability to secrete IL-10. Importantly, transfer of wild-type but not Il10rb−/− anti-inflammatory macrophages ameliorated colitis induction by wild-type CD4+ T cells in Rag2−/−Il10rb−/− mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early-onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

• Improved adaptive immune responses in humanized mice lacking murine MHC II and expressing human HLADR1.• NOD.Prkdc H2-Ab1 2/2Tg(HLA-DR1) mice reconstituted with hematopoietic stem cells from an IPEX syndrome patient develop fatal autoimmunity.Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics. (Blood. 2015;125(25):3886-3895)

As legless predators, snakes are unique in their ability to immobilize and kill their prey through the process of constriction, and yet how this pressure incapacitates and ultimately kills the prey remains unknown. In this study, we examined the cardiovascular function of anesthetized rats before, during and after being constricted by boas (Boa constrictor) to examine the effect of constriction on the prey's circulatory function. The results demonstrate that within 6 s of being constricted, peripheral arterial blood pressure (PBP) at the femoral artery dropped to 1/2 of baseline values while central venous pressure (CVP) increased 6-fold from baseline during the same time. Electrocardiographic recordings from the anesthetized rat's heart revealed profound bradycardia as heart rate (f H ) dropped to nearly half of baseline within 60 s of being constricted, and QRS duration nearly doubled over the same time period. By the end of constriction (mean 6.5±1 min), rat PBP dropped 2.9-fold, f H dropped 3.9-fold, systemic perfusion pressure (SPP=PBP−CVP) dropped 5.7-fold, and 91% of rats (10 of 11) had evidence of cardiac electrical dysfunction. Blood drawn immediately after constriction revealed that, relative to baseline, rats were hyperkalemic (serum potassium levels nearly doubled) and acidotic (blood pH dropped from 7.4 to 7.0). These results are the first to document the physiological response of prey to constriction and support the hypothesis that snake constriction induces rapid prey death due to circulatory arrest.

Many species of snakes use constriction—the act of applying pressure via loops of their trunk—to subdue and kill their prey. Constriction is costly and snakes must therefore constrict their prey just long enough to ensure death. However, it remains unknown how snakes determine when their prey is dead. Here, we demonstrate that boas ( Boa constrictor ) have the remarkable ability to detect a heartbeat in their prey and, based on this signal, modify the pressure and duration of constriction accordingly. We monitored pressure generated by snakes as they struck and constricted warm cadaveric rats instrumented with a simulated heart. Snakes responded to the beating heart by constricting longer and with greater total pressure than when constricting rats with no heartbeat. When the heart was stopped midway through the constriction, snakes abandoned constriction shortly after the heartbeat ceased. Furthermore, snakes naive to live prey also responded to the simulated heart, suggesting that this behaviour is at least partly innate. These results are an example of how snakes integrate physiological cues from their prey to modulate a complex and ancient behavioural pattern.

Background Food allergies are a growing health problem and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was−/− mice recapitulates the pathology of a conventional disease model and/or human food allergy. Methods Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was−/− mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed and the role of the high affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was−/−Fcer1a−/− mice. Results Polysensitization to food was detected in both WAS and food allergic patients which was recapitulated in the Was−/− model. Oral administration of OVA in Was−/− mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was−/− mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was−/− mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells and basophils. Conclusions Was−/− mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.