Melissa Y. Tjota

Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation

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.

IL-33–dependent induction of allergic lung inflammation by FcγRIII signaling

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), FcγRIII, 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 FcγRIII 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 FcγRIII 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 FcγRIII 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 FcγRIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33-dependent mechanism.

The Contribution of Allergen-Specific IgG to the Development of Th2-Mediated Airway Inflammation

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 (FcγR) 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 FcγR signaling on innate immune cells. Studies of IgG and FcγRs 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 FcγR signaling on innate immune cells and how it contributes to the development of allergic immune responses.

Distinct dendritic cell subsets actively induce Th2 polarization

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.

The Role of Dendritic Cells and Monocytes in the Maintenance and Loss of Respiratory Tolerance

Promoting tolerance to inhaled antigens is an active area of study with the potential to benefit the millions of Americans currently suffering from respiratory allergies and asthma. Interestingly, not all individuals with atopy are symptomatic, arguing that sensitization alone does not lead to an allergic clinical phenotype. Respiratory dendritic cells (rDCs), classically associated with inducing inflammatory responses, can actively promote tolerance. Tolerance can be broken when inflammatory stimuli, including viral infections and other environmental exposures, inhibit rDC-mediated tolerance by allowing innocuous antigen to be presented to initiate type-2 immunity. Importantly, rDCs are composed of multiple subsets, each with a unique response to an inhaled antigen that can lead to either tolerance or inflammation. In this review, we will discuss how rDC subsets actively maintain tolerance or, alternatively, break tolerance in response to environmental cues.

ICOS protects against mortality from acute lung injury through activation of IL-5 + ILC2s

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. IPF Patients suffer from a high rate of pulmonary infections and acute exacerbations of disease that further contribute to pulmonary decline. Low expression of the inducible T-cell costimulatory molecule (ICOS) in peripheral blood mononuclear cells predicts decreased survival of IPF patients, but the mechanisms by which ICOS protects are unclear. Using a model of bleomycin-induced lung injury and fibrosis, we now demonstrate that ICOS expression enhances survival from lung injury rather than regulating fibrogenesis. Of ICOS-expressing cells, type 2 innate lymphocytes (ILC2s) are the first to respond to bleomycin-induced injury, and this expansion is ICOS dependent. Interestingly, a similar decrease in ICOS+ ILCs was found in lung tissue from IPF patients. Interleukin (IL)-5, produced primarily by ILC2s, was significantly reduced after lung injury in ICOS−/− mice, and strikingly, treatment with IL-5 protected both ICOS−/− and wild-type mice from mortality. These results imply that low ICOS expression and decreased lung ILC2s in IPF patients may contribute to poor recovery from infections and acute exacerbation and that IL-5 treatment may be a novel therapeutic strategy to overcome these defects and protect against lung injury.

IL-33 Drives Monocyte Recruitment to Lung Interstitium through Chemokine Upregulation

Tissue infiltration by circulating monocytes is a critical step in the initiation and augmentation of type 2 inflammatory responses in the lungs. Our studies demonstrate that IL-33−/− mice have a defect in monocyte extravasation from the vasculature to the lung interstitium during induction of type 2 inflammatory responses. This result suggests that monocyte migration to the lungs is IL-33 dependent, and we found that administration of exogenous recombinant IL-33 is sufficient to restore monocyte localization to the lung interstitium. Further investigation of the effect of early administration of recombinant IL-33 on the lungs identified upregulation of multiple chemokines including the monocyte chemoattractants CCL2, CCL7, and CCL22. Importantly, blockade of G-protein coupled receptor–dependent signaling, and thereby chemokine receptor activity, inhibited IL-33–driven monocyte recruitment. CCR2 deficiency prevented recruitment of monocytes to the lung extravascular space during allergic sensitization, and resulted in reduced eosinophilia after allergen challenge. Thus, IL-33 plays a critical role in the initiation of type 2 inflammatory responses by inducing upregulation of chemokines that promote monocyte recruitment to the lung interstitium.