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Abstract
BackgroundIn order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self. This educational program is, to a large extent, mediated by medullary thymic epithelial cells that have a unique capacity to express, and subsequently present, a large fraction of body antigens. While the scope of promiscuously expressed genes by medullary thymic epithelial cells is well-established, relatively little is known about the expression of variants that are generated by co-transcriptional and post-transcriptional processes.ResultsOur study reveals that in comparison to other cell types, medullary thymic epithelial cells display significantly higher levels of alternative splicing, as well as A-to-I and C-to-U RNA editing, which thereby further expand the diversity of their self-antigen repertoire. Interestingly, Aire, the key mediator of promiscuous gene expression in these cells, plays a limited role in the regulation of these transcriptional processes.ConclusionsOur results highlight RNA processing as another layer by which the immune system assures a comprehensive self-representation in the thymus which is required for the establishment of self-tolerance and prevention of autoimmunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1079-9) contains supplementary material, which is available to authorized users.
Highlights
In order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self
We performed a comparative analysis of RNA-seq datasets obtained from different medullary thymic epithelial cells (mTECs) populations as well as ten different tissues and epithelial cell populations, including brain, testes, liver, kidney, lung, colon, skeletal muscle, spleen, cortical thymic epithelial cells, and skin epithelial cells [32, 33]
The mTEC populations included: (1) MHC-II low mTECs, which mainly represent an immature mTEC population; (2) MHC-II high mTECs, mainly representing a mature population; and (3) an Aire-deficient mTEChi population (AireKO), which is severely impaired in promiscuous gene expression
Summary
In order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self This educational program is, to a large extent, mediated by medullary thymic epithelial cells that have a unique capacity to express, and subsequently present, a large fraction of body antigens. Central tolerance is established in the thymus, where immature T lymphocytes are instructed by thymic stroma to become immunocompetent cells capable of recognizing foreign invaders while tolerating the body’s own components This process is primarily mediated by both negative selection of potentially self-reactive T cell clones and the induction of CD25+, Foxp3+ T regulatory (Treg) cells by various thymus-resident antigen-presenting cells [1]. A common consequence of AS in metazoans is insertion or deletion of entire segments of a protein as a result of an in-frame cassette exon insertion or exclusion [13]
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