Community Research and Development Information Service - CORDIS


CADET — Result In Brief

Project ID: 294212
Funded under: FP7-PEOPLE
Country: France

Molecular regulation of immunological tolerance

The immune system learns how to fight against invaders and at the same time tolerate body components. This intriguing capacity is carefully regulated at multiple levels.
Molecular regulation of immunological tolerance
Immunological tolerance is the mechanism by which the immune system gets educated to recognise body proteins as self and not elicit responses. The process entails presentation to the maturing T lymphocytes in the thymus while its deregulation promotes the occurrence of life-threatening autoimmune diseases.

Regulation of immunological tolerance is mediated at the transcriptional level with the activator protein called autoimmune regulator (Aire) playing a key role. Aire induces medullary epithelial cells (MECs) in the thymus to synthesise and present a large repertoire of peripheral self-antigens. This leads to the clonal deletion of self-reactive maturing T cells and thereby protects against autoimmune manifestations.

The scope of the EU-funded CADET (Post-transcriptional control of the Aire-driven expression of self-antigens in the thymus) project was to describe further the mechanism of Aire-mediated regulation of immune tolerance and identify key molecular players. Previous findings of the consortium indicated that post-transcriptional regulation in MECs occurs via microRNAs, which downregulate gene expression through the specific degradation of messenger RNAs.

Researchers discovered that the Aire protein induces the expression of a number of antigens that escape post-transcriptional repression and thus get presented to the maturing lymphocytes. Additionally, they identified the RNA-binding factor CLP1 as an interacting protein of Aire. CLP1 worked by degrading long transcripts and hence preventing their recognition by microRNAs.

Taken together, project results provide important insight into the mode of action of Aire and of immunological tolerance in general. They point towards new therapeutic interventions against autoimmune diseases such as modulation of the RNA interference pathway in MECs for enhancing self-antigen expression and presentation in the thymus. Furthermore, the identification of CLP1 underscores the role of promiscuous expression and especially the escape of microRNA-mediated repression in other systems, like cancer cells.

Related information


Regulation, immunological tolerance, T lymphocytes, thymus, Aire, medullary epithelial cells, CLP1
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