Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of TH9 cells to promote allergic inflammation

Allergic diseases are a major global health issue. Interleukin (IL)-9-producing helper T (T H 9) cells promote allergic inflammation, yet T H 9 cell effector functions are incompletely understood because their lineage instability makes them challenging to study. Here we found that resting T H 9 cells produced IL-9 independently of T cell receptor (TCR) restimulation, due to STAT5- and STAT6-dependent bystander activation. This mechanism was seen in circulating cells from allergic patients and was restricted to recently activated cells. STAT5-dependent Il9 / IL9 regulatory elements underwent remodeling over time, inactivating the locus. A broader ‘allergic T H 9’ transcriptomic and epigenomic program was also unstable. In vivo, T H 9 cells induced airway inflammation via TCR-independent, STAT-dependent mechanisms. In allergic patients, T H 9 cell expansion was associated with responsiveness to JAK inhibitors. These findings suggest that T H 9 cell instability is a negative checkpoint on bystander activation that breaks down in allergy and that JAK inhibitors should be considered for allergic patients with T H 9 cell expansion. Schwartz and colleagues show that T H 9 cells can respond to bystander cytokines IL-2 and IL-4 to induce antigen-independent expression of IL-9, promoting allergic inflammation. Il9 locus remodeling causes T H 9 cell instability, preventing antigen-independent activation in individuals who are nonallergic. Therapeutic targeting of the STAT5/STAT6 activation cascade may provide relief for patients with chronic allergy.