IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33

Abstract

Impaired tolerance to innocuous particles during allergic asthma has been linked to increased plasticity of FoxP3 + regulatory T cells (Tregs) reprogramming into pathogenic effector cells, thus exacerbating airway disease. However, failure of tolerance mechanisms is driven by Th2 inflammatory signals. Therefore, the in vivo role of canonical IL-4 receptor α (IL-4Rα) signaling, an essential driver of Th2-type airway responses to allergens, on the regulatory function of FoxP3 + Tregs in allergic asthma was explored. Here, we used transgenic Foxp3 cre IL-4Rα –/lox and littermate control mice to investigate the role of IL-4 and IL-13 signaling via Tregs in house dust mite–induced (HDM-induced) allergic airway disease. We sensitized mice intratracheally on day 0, challenged them on days 6–10, and analyzed airway hyperresponsiveness (AHR), airway inflammation, mucus production, and cellular profile on day 14. In the absence of IL-4Rα responsiveness on FoxP3 + Tregs, exacerbated AHR and airway inflammation were shown in HDM-sensitized mice. Interestingly, reduced induction of FoxP3 + Tregs accompanied increased IL-33 alarmin production and type 2 innate lymphoid cell activation in the lung, exacerbating airway hyperreactivity and lung eosinophilia. Taken together, our findings indicate that IL-4Rα–unresponsive FoxP3 + Tregs result in exaggerated innate Th2-type, IL-33–dependent airway inflammation and a break in tolerance during allergic asthma.

T regulatory cells from atopic asthmatic individuals show a Th2‐like phenotype

“…Previously, it was shown in mice that IL-4 receptor signaling is essential in controlling Th2 responses and airway inflammation. 5 Our data suggest a similar role of IL4RA in humans. Likewise, we observed a downregulation of TNF receptor superfamily member 25 (TNFRSF25), which was shown to contribute to preventing allergic lung inflammation 6 and downregulation of OX40 (TNFRSF4) and the type 1 IFN receptors IFNAR1/2 in asthmatic individuals (Figure 1B).…”

Neural Regulation of Interactions between Group 2 Innate Lymphoid Cells and Pulmonary Immune Cells

“…Previous studies on the lung ILC2 have been mainly performed in models of allergic disease [205][206][207][208], helminth infection [16,50,209,210], and septic lung injury [17,85,211,212]. Multiple neural pathways have been reported to be involved in these disease models [4,213,214].…”

Neural Regulation of Interactions Between Group 2 Innate Lymphoid Cells and Pulmonary Immune Cells

“…Previous studies on the lung ILC2 have been mainly performed in models of allergic disease (205)(206)(207)(208), helminth infection (16,50,209,210), and septic lung injury (17,85,211,212). Multiple neural pathways have been reported to be involved in these disease models (4,213,214).…”