Cel Immunological tolerance is essential in preventing autoimmunity. The establishment of T-cell tolerance is induced in the thymus mainly by the deletion of hazardous autoreactive T cells. Medullary thymic epithelial cells (mTECs) are critical in this process because they express a diverse repertoire of peripheral tissue-restricted self-antigens (TRAs). Hazardous developing T-cells recognizing these TRAs with a high affinity are deleted. TRA expression is regulated by a transcription factor: the autoimmune regulator, Aire. I have demonstrated that antigen (Ag)-specific interactions with autoreactive CD4+ thymocytes play a privileged role in governing the differentiation of Aire+ mTECs. Although these cell interactions are of pivotal importance for T-cell tolerance induction, the underlying molecular mechanisms remain to be characterized. This proposal will define the affinity threshold required for driving CD4+ thymocytes mediated Aire+ mTEC differentiation. We will particularly determine whether mTEC differentiation is coupled to deletion of autoreactive CD4+ thymocytes or whether it corresponds to a dissociable event. We will investigate the epigenetic regulation and the gene expression program that drive the differentiation of Aire+ mTECs induced by CD4+ thymocyte interactions. For this, we will take advantage of genetically modified mice in which Ag presentation to CD4+ T cells is selectively abrogated in mTECs. A particular emphasis will be given to the molecular and epigenetic regulation of the Aire gene locus. This work will entail the use of cutting edge techniques in molecular biology (e.g. ChIP-seq or RNA-seq) and in cellular biology (e.g. fetal thymic organoculture) and will involve the use of unique transgenic mouse models. Overall, the combination of these tools will allow us to dissect the molecular mechanisms that drive proper mTEC differentiation, which is essential for ensuring central T-cell tolerance and hence for protecting from autoimmunity. Dziedzina nauki natural sciencesbiological sciencescell biologycell signalingnatural sciencesbiological sciencesgeneticsepigeneticsnatural sciencesbiological sciencesmolecular biology Program(-y) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Temat(-y) FP7-PEOPLE-2013-CIG - Marie-Curie Action: "Career Integration Grants" Zaproszenie do składania wniosków FP7-PEOPLE-2013-CIG Zobacz inne projekty w ramach tego zaproszenia System finansowania MC-CIG - Support for training and career development of researcher (CIG) Koordynator INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE Wkład UE € 100 000,00 Adres RUE DE TOLBIAC 101 75654 Paris Francja Zobacz na mapie Region Ile-de-France Ile-de-France Paris Rodzaj działalności Research Organisations Kontakt administracyjny Veronique Legros (Mrs.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych