Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible T_reg cells [iT_reg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3⁺ iT_reg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3⁺ T_reg cells. T_reg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iT_reg cells coincident with blocking airway tolerance. Suppression of T_reg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma.

Summary: Helper CD4⁺ T‐cell subsets have improved our understanding of adaptive immunity in humans and in animal models of disease. These include T helper type 1 (Th1), Th2 and the interleukin‐17 (IL‐17) ‐producing population ‘Th17’. Th2 cells have been described as orchestrating the immune response in allergic disease based on studies with patient samples and animal models. The cytokine IL‐9 has largely been regarded as a Th2 cytokine that makes multifocal contributions to allergic disease. Recent data suggest that under certain conditions relevant to chronic disease (IL‐4 and transforming growth factor‐β), a distinct population of IL‐9‐producing ‘Th9’ helper T cells can exist. The contribution of Th9 cells in allergic disease is currently unknown, and this review will propose a model for how these cells may regulate chronic allergic inflammation.

Significance: Because the SNP linking chromosome 17q21 to asthma is associated with increased gasdermin B (GSDMB) expression, we generated transgenic mice expressing increased levels of the human GSDMB transgene (hGSDMB ^Zp3-Cre ), which develop an asthma phenotype characterized by a spontaneous increase in airway responsiveness and airway remodeling (increased peribronchial smooth muscle) in the absence of the development of airway inflammation. These results challenge the current paradigm in asthma that airway inflammation induces smooth muscle remodeling and airway responsiveness, as these hGSDMB ^Zp3-Cre mice develop increased airway-hyperresponsiveness and smooth muscle in the absence of airway inflammation. Furthermore, this study adds to our understanding of gene networks in asthma that we have identified can act in sequential pathways (i.e., GSDMB induces 5-lipoxygenase to induce TGF-β1).

Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6–deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.