An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to T _H17-like cells

Abstract

Mechanisms by which regulatory T (T _reg) 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 T _reg (iT _reg) cells towards a T helper 17 (T _H17) 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. T _reg cell-specific deletion of Il6ra or Rorc, but not Il4 or Il13, prevented exacerbated airway inflammation in Il4ra ^R576 mice. Furthermore, treatment of Il4ra ^R576 mice with a neutralizing anti-IL-6 antibody prevented iT _reg cell reprogramming into T _H17-like cells and protected against severe airway inflammation. These findings identify a novel mechanism for the development of mixed T _H2-T _H17 cell inflammation in genetically prone individuals, and point to interventions that stabilize iT _reg cells as potentially effective therapeutic strategies.