An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells
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Date
2016
Author(s)
Massoud, Amir Hossein
Lopez, David
Pellegrini, Matteo
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Citation
Massoud, Amir Hossein, Louis-Marie Charbonnier, David Lopez, Matteo Pellegrini, Wanda Phipatanakul, and Talal A Chatila. 2016. “An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells.” Nature medicine 22 (9): 1013-1022. doi:10.1038/nm.4147. http://dx.doi.org/10.1038/nm.4147.
Abstract
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 interleukin-4 receptor alpha chain (IL4RA R576) promotes conversion of induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4Rα-R576 of the growth factor receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway involving extracellular signal-regulated kinase, IL-6 and STAT3. Treg cell-specific deletion of Il6ra or Rorc, but not Il4 or Il13, prevented exacerbated airway inflammation in Il4raR576 mice. Furthermore, treatment of Il4raR576 mice with a neutralizing anti-IL-6 antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a novel 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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