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

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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 theIl17locus 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 functionsin 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 promotingIl17aandIl17fexpression. Etv5 recruits histone-modifying enzymes to theIl17a-Il17flocus, resulting in increased active histone marks and decreased repressive histone marks. In a model of allergic airway inflammation, mice withEtv5-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.

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