The Ets-1 transcription factor controls the development and function of natural regulatory T cells

E Mouly, K Chemin, HV Nguyen, M Chopin… - Journal of Experimental …, 2010 - rupress.org
E Mouly, K Chemin, HV Nguyen, M Chopin, L Mesnard, M Leite-de-Moraes
Journal of Experimental Medicine, 2010rupress.org
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 …
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.
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