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Post-transcriptional Control of the Aire-Driven expression of self-antigens in the Thymus

Final Report Summary - CADET (Post-transcriptional Control of the Aire-Driven expression of self-antigens in the Thymus)

The main function of the immune system is to fight against infections in recognizing foreign constituents. But the immune system also needs to tolerate our body’s own proteins (the self-antigens or auto-antigens) through a mechanism called immunological tolerance. The completion of this project provides decisive insights into the understanding of how our self-constituents are presented to the maturing lymphocytes in the thymus, with the goal to educate them to the self in order to avoid the occurrence of autoimmune diseases.
The first main finding that this project revealed is an important additional layer of control of self-antigen expression in the thymus, occurring at the post-transcriptional level. The project revealed that the post-transcriptional regulation in the cells that express the self in the thymus (the MECs), is mediated by small RNAs called miRNAs that accumulate to set a cellular repressive milieu leading to downregulation of gene expression by the specific degradation of mRNAs.
This project revealed that the AIRE protein or (Autoimmune Regulator) induces a wide array or self-antigens whose mRNAs have the ability to escape this post-transcriptional repression, resulting in their higher relative expression and enhanced presentation to the mature lymphocytes. The involvement of miRNAs in the control of self-antigen expression in the thymus suggest potential new therapeutic approaches to fight against autoimmune diseases, notably a MEC-specific delivery of short hairpin RNAs targeting Drosha and whose knockdown would impair the entire RNAi pathway. This would result in the enhancement of self-antigen expression and presentation to maturing lymphocytes in the thymus.
The other main finding that this project revealed is the identification of CLP1, an RNA-binding factor, that plays a key role in this mechanism and that interacts with AIRE. This research showed that CLP1 is involved in the miRNA-mediated post-transcriptional repression, resulting in the degradation of transcripts with long RNA sequences susceptible to be recognized by miRNAs and thereby in a higher proportion of short transcripts that can be preferentially presented to the immunological cells. The identification of CLP1 could also provide a new therapeutic target to potentially re-establish immune tolerance in deficient individuals. Altogether these results should provide invaluable insights into the mode of action of AIRE and into the fine understanding of immunological tolerance in the thymus.
In addition to be of considerable interest into the understanding of promiscuous expression, the identification of CLP1 may also help to understand the escape of the miRNA-mediated repression in other systems, like in cancer cells. Indeed, since CLP1 like other RNA-binding factors recruited by AIRE are general effectors, it will be worthwhile testing their impact on oncogene expression and malignant transformation. As this is an epigenic mechanism, it could theoretically be reversed, perhaps providing a new strategy for cancer treatment using specific inhibitors of the post-transcriptional repression.