An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to T(H)17-like cells

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(H)17) 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(H)17-like cells and protected against severe airway inflammation. These findings identify a novel mechanism for the development of mixed T(H)2-T(H)17 cell inflammation in genetically prone individuals, and point to interventions that stabilize iT(reg) cells as potentially effective therapeutic strategies.