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

被引:16
作者
Khumalo, Jermaine [1 ,2 ,3 ,5 ]
Kirstein, Frank [1 ,2 ]
Hadebe, Sabelo [1 ,2 ]
Brombacher, Frank [1 ,2 ,3 ,4 ]
机构
[1] Univ Cape Town, Div Immunol, Fac Hlth Sci, Anzio Rd, ZA-7925 Cape Town, South Africa
[2] Univ Cape Town, Fac Hlth Sci, South African Med Res Council SAMRC Immunol Infec, Dept Pathol, Cape Town, South Africa
[3] Univ Cape Town, Fac Hlth Sci, Int Ctr Genet Engn & Biotechnol ICGEB, Cape Town, South Africa
[4] Univ Cape Town, Wellcome Ctr Infect Dis Res Africa CIDRI Africa, Inst Infect Dis & Mol Med IDM, Fac Hlth Sci, Cape Town, South Africa
[5] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA USA
基金
英国医学研究理事会; 新加坡国家研究基金会; 英国惠康基金;
关键词
INNATE LYMPHOID-CELLS; FOOD ALLERGY; HELPER-CELLS; IN-VIVO; TOLERANCE; PROMOTES; IMMUNITY; INTERLEUKIN-33; ACTIVATION; INDUCTION;
D O I
10.1172/jci.insight.136206
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
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页数:15
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