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  • Periodic Report Summary 1 - SIGNEPI4TOL (Cell signaling pathways and epigenetic mechanisms controlling the differentiation of medullary thymic epithelial cells, key mediators in the induction of central self-tolerance)

Periodic Report Summary 1 - SIGNEPI4TOL (Cell signaling pathways and epigenetic mechanisms controlling the differentiation of medullary thymic epithelial cells, key mediators in the induction of central self-tolerance)

The immune system possesses the fascinating capacity to discriminate self from non-self, which is essential to prevent the development of autoimmune disorders. This exclusive property is called the “immunological tolerance”. The thymus provides a unique stromal microenvironment that controls the development of functional T cells that are both self-tolerant and able to respond to foreign pathogens. This capacity to discriminate self from non-self is primarily instructed by thymic epithelial cells (TECs). Cortical TECs (cTECs) initiate early stages of T-cell development including the differentiation into CD4+ and CD8+ T cells whereas medullary TECs (mTECs) by expressing a wide range of tissue-restricted self-antigens (TRAs) play a key role in purging the repertoire of hazardous autoreactive T cells and in inducing Foxp3+ regulatory T cells. Two transcription factors, Aire (Autoimmune Regulator) and Fezf2 (Forebrain Expressed Zinc Finger 2), have been identified so far for regulating TRA expression. While mTECs control the selection of developing T cells in shaping their TCR repertoire, conversely T cells control the differentiation of mTECs, a process referred to as “thymic crosstalk”. My previous works have shown that mTEC differentiation and organization are controlled by antigen (Ag)-specific interactions with CD4+ T cells. Although these cell interactions are of pivotal importance for the generation of Aire+ mTECs and thus for the establishment of T-cell tolerance, the underlying molecular mechanisms remain unknown. The objective of this EU-funded SIGnEPI4Tol project is to decipher the molecular and epigenetic mechanisms by which Ag-specific interactions with CD4+ T cells regulate mTEC biology. By using unique transgenic mouse models, in which Ag presentation to CD4+ T cells is selectively abrogated in mTECs, and high-throughput RNA-sequencing, we have discovered that the crosstalk with CD4+ T cells regulates several unsuspected functional properties of mTECs such as the expression of (i) numerous TRAs involved in T-cell repertoire selection, (ii) chemokines, involved in the trafficking of developing T cells and dendritic cells and (iii) adhesion molecules involved in mTEC-T cell interactions. Taken together, the results obtained during the course of this project provide important insights into the mode of action of the crosstalk with CD4+ T cells to control the generation of a functional mTEC population capable of ensuring the induction of central T-cell tolerance. We anticipate that the results obtained should pave the way for developing new therapeutic strategies to ameliorate qualitatively and quantitatively T-cell development, which is of special interests for treating thymus-linked autoimmune disorders.

Website: http://cvscience.aviesan.fr/cv/1387/magali-irla

Contact: Dr. Magali Irla; PhD, HDR
Inserm CR1
Centre d'Immunologie de Marseille-Luminy (CIML)
Magali.Irla@inserm.fr

Contact

Veronique LEGROS, (Agent comptable secondaire)
Tel.: +33491827015
Fax: +33491827048
E-mail

Subjects

Life Sciences
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