TOLERANCE FOOTPRINT
Financiado
Clonal Deletion versus Clonal Diversion Footprints of Self Tolerance in the T C...
Clonal Deletion versus Clonal Diversion Footprints of Self Tolerance in the T Cell Repertoire
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: potentia...
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.
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Duración del proyecto: 62 meses
Fecha Inicio: 2017-07-05
Fecha Fin: 2022-09-30
Fecha Fin: 2022-09-30
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2022-09-30
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2016-ADG:
ERC Advanced Grant
Cerrada
hace 8 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
LUDWIGMAXIMILIANSUNIVERSITAET MUENCHEN
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
842.61K€ |
Participante