A Common IL ‐4 Receptor Variant Promotes Asthma Severity via a T _reg Cell GRB2‐IL‐6‐Notch4 Circuit

Background The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL‐4 receptor alpha chain R576 (IL‐4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (T reg ) cells in an IL‐6‐dependent manner. Objective We examined the interaction between IL‐4RαR576 and Notch4 in promoting asthmatic inflammation. Methods Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on T reg cells as a function of IL4R R576 allele. The capacity of IL‐4RαR576 to upregulate Notch4 expression on T reg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. Results Asthmatics carrying the IL4R R576 allele had increased Notch4 expression on their circulating T reg cells as a function of disease severity and serum IL‐6. Mice harboring the Il4ra R576 allele exhibited increased Notch4‐dependent allergic airway inflammation that was inhibited upon T reg cell‐specific Notch4 deletion or treatment with an anti‐Notch4 antibody. Signaling via IL‐4RαR576 upregulated the expression in lung T reg cells of Notch4 and its downstream mediators Yap1 and beta‐catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor‐bound protein 2 (GRB2) and IL‐6 receptor. Conclusion These results identify an IL‐4RαR576‐regulated GRB2‐IL‐6‐Notch4 circuit that promotes asthma severity by subverting lung T reg cell function.