Journal
JCI INSIGHT
Volume 5, Issue 20, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.136206
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Funding
- ICGEB
- Medical Research Council (MRC) South Africa
- South African National Research Foundation (NRF) Research Chair initiative (SARChi)
- NRF Thuthuka Grant
- MRC Self-initiated Research Grant
- Robert Bosch Stiftung Fellowship
- NRF Competitive Program for Unrated Researchers (CSUR)
- Cape Town Component
- Wellcome Trust CIDRI-Africa [203135Z/16/Z]
- SARChi PhD studentship
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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 alpha (IL-4R alpha) 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-4R alpha(-/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-4R alpha 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-4R alpha-unresponsive FoxP3(+) Tregs result in exaggerated innate Th2-type, IL-33-dependent airway inflammation and a break intolerance during allergic asthma.
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