Abstract
The ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3'end processing complex, suggesting they might impact transcript stability and levels through an effect on 3'UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3'UTR transcript isoforms in mTECs, a feature preceding Aire's expression and correlated with the preferential selection of proximal polyA sites by the 3'end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3'UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.
Highlights
Immunological tolerance is a key feature of the immune system that protects against autoimmune disease by preventing immune reactions against self-constituents
To determine whether the Aire-sensitive genes exhibit a biased proportion of long and short-3’UTR isoforms in mTEChi, we first performed RNA deep-sequencing (RNA-seq) of mTEChi sorted from WT and Aire-KO mice in order to identify the Aire-sensitive genes, that is those upregulated by Aire (Figure 1B and Figure 1—source data 2)
We found a significant shift towards smaller ratios, revealing a preference of Aire-sensitive genes for short-3’UTR isoforms in mTEChi (Figure 1C, Figure 1—figure supplement 1A and Figure 1—source data 3 and 4)
Summary
Immunological tolerance is a key feature of the immune system that protects against autoimmune disease by preventing immune reactions against self-constituents. Central tolerance is shaped in the thymus and relies on a unique property of a subset of medullary thymic epithelial cells (mTECs). This subset is composed of mTEChi that express high levels of MHC class II molecules and a huge diversity of self-antigens (Danan-Gotthold et al, 2016; Kyewski and Klein, 2006). Developing T lymphocytes in the thymus are exposed to a broad spectrum of self-antigens displayed by mTEChi. developing T lymphocytes in the thymus are exposed to a broad spectrum of self-antigens displayed by mTEChi Those lymphocytes that recognize their cognate antigens undergo either negative selection, thereby preventing the escape of potentially harmful autoreactive lymphocytes out of the thymus, or differentiate into thymic regulatory T cells beneficial for limiting autoreactivity
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