Objectif Self-tolerance is a key feature of the immune system; its failure causes autoimmune diseases such as Multiple Sclerosis or Type-1-Diabetes. Remarkably, T cell tolerance operates via two fundamentally different mechanisms: potentially dangerous cells are either eliminated (clonal deletion) or re-programmed to differentiate into regulatory T (Treg) cells (clonal diversion). Paradoxically, both tolerance modes can ensue from self-antigen-encounter in the thymus, and the parameters specifying these opposing cell-fates remain poorly understood. Moreover, the relative contribution of clonal deletion versus clonal diversion to tolerance at the level of diverse immune cell repertoires has not been determined. In particular, the paucity of antigen-specific cells is a major experimental obstacle to unravelling to what extent cells with shared autoreactive specificity, yet different T cell receptors (TCRs), are subject to either mode of tolerance.Breakthroughs in visualizing minute cohorts of antigen-specific cells, characterizing the TCRs on individual cells and large-scale TCR sequencing now provide a unique opportunity to tackle these challenging questions. Based upon my expertise in thymus biology and T cell selection, I will exploit these technological advances to reveal where and how tolerance either generates ‘holes’ in the repertoire or diverts cells into a ‘benign’ sub-repertoire. The main objectives are (i) to identify and classify deleted or diverted TCR-entities through comparing ‘uncensored’ and ‘censored’ repertoires in the absence or presence of a disease-relevant autoantigen and (ii) to identify TCR intrinsic features as well as T cell extrinsic determinants that specify clonal deletion versus clonal diversion.The proposed research elucidates a fundamental aspect of vertebrate immunology, but also has major implications regarding the therapeutic promise of harnessing endogenous, antigen-specific Treg cells in autoimmunity. Champ scientifique medical and health sciencesbasic medicineneurologymultiple sclerosismedical and health sciencesbasic medicineimmunologyautoimmune diseases Mots‑clés T cell tolerance T cell repertoire Thymus Clonal deletion Regulatory T cell Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-2016-ADG - ERC Advanced Grant Appel à propositions ERC-2016-ADG Voir d’autres projets de cet appel Régime de financement ERC-ADG - Advanced Grant Institution d’accueil LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Contribution nette de l'UE € 2 414 500,00 Adresse GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Allemagne Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 414 500,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Allemagne Contribution nette de l'UE € 2 414 500,00 Adresse GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 414 500,00
