Pulmonary Epithelial Cell-Derived Cytokine TGF-β1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function

Abstract

SummaryEpithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions.

Early local immune defences in the respiratory tract

“…While both IL-33 and IL-25 can promote ILC2 proliferation, studies in mouse models of airway hyperresponsiveness suggest that IL-33 is a more potent activator of these cells in vivo than IL-25 66 , and that IL-25 activates a subset of innate lymphoid precursor cells that can be induced to differentiate into ILC2 or ILC3 cells 67,68 . TGFβ, but not IL-33, enhances ILC2 basal migration rates, priming ILC2s to respond to additional chemotactic stimuli in the airways 49 . Human ILC2s are also responsive to IL-1α/β, and IL-1 signaling enhances the expression of the receptors for IL-33, IL-25, and TSLP; thus, IL-1 is important for priming and amplifying the responsiveness of ILC2s to first order cytokines in the context of an unresolved infection 69 .…”

“…In mouse alveoli, alveolar type II epithelial cells are the primary source of IL-33 and TSLP during helminth infection, which is consistent with their role as cytokine producing cells 48 . More recently, secretion of TGFβ from AECs was shown to be essential during mouse allergic responses by acting on local ILC2s to enhance their proliferation and cytokine secretion 49 (Figure 4B). …”

“…They proliferate and produce the canonical type 2 cytokines IL-5 and IL-13 during both helminth infections 64 and allergic responses 65 in mice. ILC2s constantly survey the airway epithelium and are highly responsive to AEC-derived cytokines including IL-33, IL-25, TSLP, and TGFβ 49,64,65 . While both IL-33 and IL-25 can promote ILC2 proliferation, studies in mouse models of airway hyperresponsiveness suggest that IL-33 is a more potent activator of these cells in vivo than IL-25 66 , and that IL-25 activates a subset of innate lymphoid precursor cells that can be induced to differentiate into ILC2 or ILC3 cells 67,68 .…”

MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction

“…Our preliminary results have demonstrated that inhibition of MAP3K19 had no effect on the respiratory burst or phagocytosis of macrophages (data not shown). However, recent results may help explain this finding, in which it was shown that decreased TGF-β levels following respiratory viral infection allow IFN-β levels to rise quickly, which leads to a decrease in virus production [48, C. Lloyd, pers. commun.].…”

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

“…Furthermore, in eosinophilic crystalline pneumonia, a murine idiopathic type 2 lung inflammation, IL-2 was shown to function as an important activator of ILC2 functions; the authors further highlight a potential cross talk between ILC2 and ILC3 as well as T cells and T reg during disease pathogenesis (100). Even more important, in a murine model for allergic asthma, pulmonary epithelial cell-derived TGF-β1 and IL-33 contributed to ILC2-mediated responses (101). …”