The transcription factor Etv5 controls TH17 cell development and allergic airway inflammation.
BACKGROUND
The differentiation of TH17 cells, which promote pulmonary inflammation, requires the cooperation of a network of transcription factors.


OBJECTIVE
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 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 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.
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind.
Duy
D
Pham
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind.
Sarita
S
Sehra
Laboratory of Genetics, University of Wisconsin-Madison, Wis.
Xin
X
Sun
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind. Electronic address: mkaplan2@iupui.edu.
Mark H
MH
Kaplan
D000485:Allergens / Q000737:chemistry / Q000276:immunology; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D056426:Genetic Loci; D005822:Genetic Vectors; D006657:Histones / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D011014:Pneumonia / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D039981:Pyroglyphidae / Q000737:chemistry / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012190:Retroviridae / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
D000485:Allergens; D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D006657:Histones; C098680:Il17a protein, mouse; C515932:Il17f protein, mouse; D020381:Interleukin-17; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors
Etv5; T(H)17 cells; allergic inflammation; epigenetic modifications; transcription factor