The Ets-1 transcription factor controls the development and function of natural regulatory T cells.
Regulatory T cells (T reg cells) constitute a population of CD4(+) T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1(-/-)) developed T cell-mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1(-/-) mice contained mostly activated T cells, including Th2-polarized CD4(+) cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1(-/-) T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1(-/-) T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1(-/-) T reg cells showed decreased in vitro suppression activity and did not protect Rag2(-/-) hosts from naive T cell-induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression.
Mouly
Enguerran
E
EA3963, Université Paris 7 Denis Diderot, Institut National de la Santé et de la Recherche Médicale, Institut Fédératif de Recherche 105, Institut Universitaire d'Hématologie, 75475 Paris, France.
Chemin
Karine
K
Nguyen
Hai Vu
HV
Chopin
Martine
M
Mesnard
Laurent
L
Leite-de-Moraes
Maria
M
Burlen-defranoux
Odile
O
Bandeira
Antonio
A
Bories
Jean-Christophe
JC
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation; D002678:Chimera / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000276:immunology; D039001:Integrin alpha Chains / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013163:Splenomegaly / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039001:Integrin alpha Chains; D050784:Proto-Oncogene Protein c-ets-1; C499308:Rag2 protein, mouse; C091367:alpha E integrins