TGFβR signalling determines CD103⁺CD11b⁺ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs

Rapid fucosylation of intestinal epithelium sustains host–commensal symbiosis in sickness

Systemic infection induces conserved physiological responses that include both resistance and ‘tolerance of infection’ mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections). We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host’s resources to maintain host–microbial interactions during pathogen-induced stress

Macrophages in intestinal homeostasis and inflammation

The intestine contains the largest pool of macrophages in the body which are essential for maintaining mucosal homeostasis in the face of the microbiota and the constant need for epithelial renewal but are also important components of protective immunity and are involved in the pathology of inflammatory bowel disease (IBD). However, defining the biological roles of intestinal macrophages has been impeded by problems in defining the phenotype and origins of different populations of myeloid cells in the mucosa. Here, we discuss how multiple parameters can be used in combination to discriminate between functionally distinct myeloid cells and discuss the roles of macrophages during homeostasis and how these may change when inflammation ensues. We also discuss the evidence that intestinal macrophages do not fit the current paradigm that tissue-resident macrophages are derived from embryonic precursors that self-renew in situ, but require constant replenishment by blood monocytes. We describe our recent work demonstrating that classical monocytes constantly enter the intestinal mucosa and how the environment dictates their subsequent fate. We believe that understanding the factors that drive intestinal macrophage development in the steady state and how these may change in response to pathogens or inflammation could provide important insights into the treatment of IBD

Effects of Prior Knowledge in Mathematics on Learner-Interface Interactions in a Learning-by-Teaching Intelligent Tutoring System

This study attempted to determine the influence of prior knowledge in mathematics of students on learner-interface interactions in a learning-by-teaching intelligent tutoring system. One hundred thirty-nine high school students answered a pretest (i.e., the prior knowledge in mathematics) and a posttest. In between the pretest and posttest, they used the SimStudent, an intelligent tutoring system that follows a teaching-by-learning paradigm. The intervention period lasted for three consecutive days with 1 hour session each. SimStudent captured learner-interface interactions, such as time spent tutoring, number of quizzes conducted, and number of hints requested. It was disclosed that prior knowledge in term identification was the only skill that had a consistent, positive, and significant influence on learner-interface interaction with a SimStudent. Thus, the null hypothesis stating that prior knowledge in mathematics does not significantly influence interaction of students with a simulated student was partially rejected. It was concluded that the students may demonstrate or omit a skill, depending on their prior knowledge on identifying the terms of equations and the next step in solving equations. Recommendations and directions for future studies were presented

Immunomodulation by Bifidobacterium infantis 35624 in the murine lamina propria requires retinoic acid-dependent and independent mechanisms

Appropriate dendritic cell processing of the microbiota promotes intestinal homeostasis and protects against aberrant inflammatory responses. Mucosal CD103(+) dendritic cells are able to produce retinoic acid from retinal, however their role in vivo and how they are influenced by specific microbial species has been poorly described. Bifidobacterium infantis 35624 (B. infantis) feeding to mice resulted in increased numbers of CD103(+)retinaldehyde dehydrogenase (RALDH)(+) dendritic cells within the lamina propria (LP). Foxp3(+) lymphocytes were also increased in the LP, while TH1 and TH17 subsets were decreased. 3,7-dimethyl-2,6-octadienal (citral) treatment of mice blocked the increase in CD103(+)RALDH(+) dendritic cells and the decrease in TH1 and TH17 lymphocytes, but not the increase in Foxp3(+) lymphocytes. B. infantis reduced the severity of DSS-induced colitis, associated with decreased TH1 and TH17 cells within the LP. Citral treatment confirmed that these effects were RALDH mediated. RALDH(+) dendritic cells decreased within the LP of control inflamed animals, while RALDH(+) dendritic cells numbers were maintained in the LP of B. infantis-fed mice. Thus, CD103(+)RALDH(+) LP dendritic cells are important cellular targets for microbiota-associated effects on mucosal immunoregulation

Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1

The mechanisms by which tumor microenvironments modulate nucleic acid-mediated innate immunity remain unknown. Here, we identified the receptor TIM-3 as key to circumventing the stimulatory effects of nucleic acids in tumor immunity. TIM-3 is highly expressed on tumor-associated dendritic cells (DC) in murine tumors and cancer patients. DC-derived TIM-3 suppresses innate immune responses through Toll-like receptor and cytosolic sensor recognition of nucleic acids via a galectin-9 independent mechanism. Instead, TIM-3 interacts with the HMGB1 to interfere with recruitment of nucleic acids into DC endosomes and attenuates the therapeutic efficacy of DNA vaccination and chemotherapy by reducing immunogenicity of nucleic acids released from dying tumor cells. Together, these findings define a novel mechanism by which tumor microenvironments suppress antitumor immunity mediated by nucleic acids

CD40-signalling abrogates induction of RORγt+ Treg cells by intestinal CD103+ DCs and causes fatal colitis

Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. CD103+ dendritic cells (DCs) acquire microbiota-derived material from the gut lumen for transport to draining lymph nodes and generation of receptor-related orphan γt+ (RORγt+) Helios−-induced Treg (iTreg) cells. Here we show CD40-signalling as a microbe-independent signal that can induce migration of CD103+ DCs from the lamina propria (LP) to the mesenteric lymph nodes. Transgenic mice with constitutive CD11c-specific CD40-signalling have reduced numbers of CD103+ DCs in LP and a low frequency of RORγt+Helios− iTreg cells, exacerbated inflammatory Th1/Th17 responses, high titres of microbiota-specific immunoglobulins, dysbiosis and fatal colitis, but no pathology is detected in other tissues. Our data demonstrate a CD40-dependent mechanism capable of abrogating iTreg cell induction by DCs, and suggest that the CD40L/CD40-signalling axis might be able to intervene in the generation of new iTreg cells in order to counter-regulate immune suppression to enhance immunity