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

Mechanisms by which regulatory T (T sub(reg)) 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 (Il4ra super(R576)) promotes conversion of induced T sub(reg) (iT sub(reg)) cells toward a T helper 17 (T sub(H)17) cell fate. This skewing is mediated by the recruitment by IL-4R alpha super(R576) 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. T sub(reg) cell-specific deletion of genes that regulate T sub(H)17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 or Il13, prevented exacerbated airway inflammation in mice expressing Il4ra super(R576) (hereafter referred to as Il4ra super(R576) mice). Furthermore, treatment of Il4ra super(R576) mice with a neutralizing IL-6-specific antibody prevented iT sub(reg) cell reprogramming into T sub(H)17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed T sub(H)2-T sub(H)17 cell inflammation in genetically prone individuals and point to interventions that stabilize iT sub(reg) cells as potentially effective therapeutic strategies.