The transcription factor Etv5 controls TH17 cell development and allergic airway inflammation

Background: The differentiation of T(H)17 cells, which promote pulmonary inflammation, requires the cooperation of a network of transcription factors. Objectives: We sought to define the role of Etv5, an Ets-family transcription factor, in T(H)17 cell development and function. Methods: T(H)17 development was examined in primary mouse T cells wherein Etv5 expression was altered by retroviral transduction, small interfering RNA targeting a specific gene, and mice with a conditional deletion of Etv5 in T cells. The direct function of Etv5 on the Il17 locus was tested with chromatin immunoprecipitation and reporter assays. The house dust mite-induced allergic inflammation model was used to test the requirement for Etv5-dependent T(H)17 functions in vivo. Results: We identify Etv5 as a signal transducer and activator of transcription 3-induced positive regulator of T(H)17 development. Etv5 controls T(H)17 differentiation by directly promoting Il17a and Il17f expression. Etv5 recruits histone-modifying enzymes to the Il17a-Il17f locus, resulting in increased active histone marks and decreased repressive histone marks. In a model of allergic airway inflammation, mice with Etv5-deficient T cells have reduced airway inflammation and IL-17A/F production in the lung and bronchoalveolar lavage fluid compared with wild-type mice, without changes in T(H)2 cytokine production. Conclusions: These data define signal transducer and activator of transcription 3-dependent feed-forward control of T(H)17 cytokine production and a novel role for Etv5 in promoting T cell-dependent airway inflammation.