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

Abstract

Background The differentiation of TH17 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 TH17 cell development and function. Methods TH17 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 TH17 functions in vivo. Results We identify Etv5 as a signal transducer and activator of transcription 3–induced positive regulator of TH17 development. Etv5 controls TH17 differentiation by directly promoting 0a 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 TH2 cytokine production. Conclusions These data define signal transducer and activator of transcription 3–dependent feed-forward control of TH17 cytokine production and a novel role for Etv5 in promoting T cell–dependent airway inflammation.