The mechanisms by which dendritic cells induce Th2 polarization (DC(Th2) cells) have been controversial. Many have argued that DC(Th2) cells are not a distinct functional DC subset, but rather, DC-induced polarization of Th2 cells is a default pathway that occurs in the absence of inflammatory signals leading to DC-induced polarization of Th1/Th17 cells. However, recent studies demonstrate that distinct subsets of tissue DCs actively polarize Th2 cells after stimulation with type-2 inducing stimuli. DC(Th2) cells development is marked by the upregulation of specific transcription factors, cell surface molecules, and cytokines. These findings counter previous hypotheses that Th2 skewing by DCs is a passive response and support a model in which DCs are actively programmed to induce Th2 differentiation.
Environmentally induced alterations in the commensal microbiota have been implicated in the increasing prevalence of food allergy. We show here that sensitization to a food allergen is increased in mice that have been treated with antibiotics or are devoid of a commensal microbiota. By selectively colonizing gnotobiotic mice, we demonstrate that the allergy-protective capacity is conferred by a Clostridia-containing microbiota. Microarray analysis of intestinal epithelial cells from gnotobiotic mice revealed a previously unidentified mechanism by which Clostridia regulate innate lymphoid cell function and intestinal epithelial permeability to protect against allergen sensitization. Our findings will inform the development of novel approaches to prevent or treat food allergy based on modulating the composition of the intestinal microbiota.
Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown.
Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.
Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG-immune complexes (IgG-ICs), Fc?RIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response. Development of Th2-type airway inflammation was shown to be both Fc?RIII and TLR4 dependent, and T cells were necessary and sufficient for this process to occur, even in the absence of type 2 innate lymphoid cells. We sought to identify downstream targets of Fc?RIII signaling that could contribute to this process and demonstrated that bone marrow-derived DCs, alveolar macrophages, and respiratory DCs significantly upregulated IL-33 when activated through Fc?RIII and TLR4. Importantly, IC-induced Th2 inflammation was dependent on the ST2/IL-33 pathway. Our results suggest that allergen-specific IgG can enhance secondary responses by ligating Fc?RIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33-dependent mechanism.
Mesenchymal stem cells (MSCs) are emerging as a promising immunotherapeutic, based largely on their overt suppression of T lymphocytes under inflammatory and autoimmune conditions. While paracrine cross-talk between MSCs and T cells has been well-studied, an intrinsic transcriptional switch that programs MSCs for immunomodulation has remained undefined. Here we show that bone marrow-derived MSCs require the transcriptional regulator Aire to suppress T cell-mediated pathogenesis in a mouse model of chronic colitis. Surprisingly, Aire did not control MSC suppression of T cell proliferation in vitro. Instead, Aire reduced T cell mitochondrial reductase by negatively regulating a proinflammatory cytokine, early T cell activation factor (Eta)-1. Neutralization of Eta-1 enabled Aire(-/-) MSCs to ameliorate colitis, reducing the number of infiltrating effector T cells in the colon, and normalizing T cell reductase levels. We propose that Aire represents an early molecular switch imposing a suppressive MSC phenotype via regulation of Eta-1. Monitoring Aire expression in MSCs may thus be a critical parameter for clinical use.
In both human asthmatics and animal models of allergy, allergen-specific IgG can contribute to Th2-mediated allergic inflammation. Mouse models have elucidated an important role for IgG and Fc-gamma receptor (Fc?R) signaling on antigen presenting cells (APC) for the induction of airway inflammation. These studies suggest a positive feedback loop between IgG produced by the adaptive B cell response and Fc?R signaling on innate immune cells. Studies of IgG and Fc?Rs in humans with asthma or allergic lung disease have been more controversial. Some reports have identified associations between allergen-specific IgG and severity of allergic responses, while other studies have found associations of IgG subclass IgG4 with allergic tolerance. In this paper, we review the literature to help define the nature of IgG and Fc?R signaling on innate immune cells and how it contributes to the development of allergic immune responses.
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