Cel 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. Dziedzina nauki medical and health sciencesbasic medicineneurologymultiple sclerosismedical and health sciencesbasic medicineimmunologyautoimmune diseases Słowa kluczowe T cell tolerance T cell repertoire Thymus Clonal deletion Regulatory T cell Program(-y) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Temat(-y) ERC-2016-ADG - ERC Advanced Grant Zaproszenie do składania wniosków ERC-2016-ADG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-ADG - Advanced Grant Instytucja przyjmująca LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Wkład UE netto € 2 414 500,00 Adres GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Niemcy Zobacz na mapie Region Bayern Oberbayern München, Kreisfreie Stadt Rodzaj działalności Higher or Secondary Education Establishments Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 414 500,00 Beneficjenci (1) Sortuj alfabetycznie Sortuj według wkładu UE netto Rozwiń wszystko Zwiń wszystko LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Niemcy Wkład UE netto € 2 414 500,00 Adres GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Zobacz na mapie Region Bayern Oberbayern München, Kreisfreie Stadt Rodzaj działalności Higher or Secondary Education Establishments Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 414 500,00
