Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4raR576) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4RαR576 of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3. Treg cell–specific deletion of genes that regulate TH17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 or Il13, prevented exacerbated airway inflammation in mice expressing Il4raR576 (hereafter referred to as Il4raR576 mice). Furthermore, treatment of Il4raR576 mice with a neutralizing IL-6-specific antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed TH2–TH17 cell inflammation in genetically prone individuals and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies.
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This work was supported by a National Institutes of Health grants R01 AI065617 (T.A.C.), U10HL098102 (W.P.) and U10HL109172 (W.P.). We thank E. Crestani, D. Schierembergg and A. Cunningham for help with patient recruitment, and H.C. Oettgen and L.-M. Charbonnier for their critical review of the manuscript.
The authors declare no competing financial interests.
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Massoud, A., Charbonnier, L., Lopez, D. et al. An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med 22, 1013–1022 (2016) doi:10.1038/nm.4147
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