Th9 cells are prominently featured in allergic lung inflammation, but the mechanism that regulates IL-9 induction in T helper cells remains poorly defined. Here we demonstrate that formation of super-enhancers (SEs) is critical in robust induction of IL-9 and that assembly of the Il9 SEs in Th cells requires OX40-triggered chromatin acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation. This allows binding of the SE factor Brd4 to organize assembly of the SE complex, which in turn drives robust IL-9 expression and Th9 cell induction. Thus, Th9 cells are strongly induced upon OX40 stimulation, and disruption of SEs abolished Th9 cell induction in vitro and inhibited Th9 cell–mediated allergic airway inflammation in vivo. Together, our data suggest that formation of SEs is essential in IL-9 expression and Th9 cell induction. These findings may have important clinical implications.

Th9细胞在过敏性肺部炎症中具有突出的特征，但是调节T辅助细胞中IL-9诱导的机制仍然不清楚。在这里，我们证明了超级增强剂（SEs）的形成对于IL-9的强大诱导至关重要，而Th9细胞中Il9 SEs的组装需要OX40触发的染色质乙酰化。从机制上讲，我们发现OX40共刺激诱导RelB表达，这将组蛋白乙酰转移酶p300募集到Il9位点催化H3K27乙酰化。这允许SE因子Brd4结合以组织SE复合物的组装，进而驱动鲁棒的IL-9表达和Th9细胞诱导。因此，在OX40刺激下强烈诱导Th9细胞，而SEs的破坏在体外废除了Th9细胞诱导，而在体内抑制Th9细胞介导的过敏性气道炎症。在一起，我们的数据表明SEs的形成在IL-9表达和Th9细胞诱导中是必不可少的。这些发现可能具有重要的临床意义。