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Lopes, Noella; Boucherit, Nicolas; Santamaria, Jérémy C; Provin, Nathan; Charaix, Jonathan; Ferrier, Pierre; Giraud, Matthieu; Irla, Magali
eLife, 02/2022, Letnik: 11Journal Article
Interactions of developing T cells with Aire medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEC ) are critical for the induction of central tolerance in the thymus. In turn, thymocytes regulate the cellularity of Aire mTEC . However, it remains unknown whether thymocytes control the precursors of Aire mTEC that are contained in mTEC cells or other mTEC subsets that have recently been delineated by single-cell transcriptomic analyses. Here, using three distinct transgenic mouse models, in which antigen presentation between mTECs and CD4 thymocytes is perturbed, we show by high-throughput RNA-seq that self-reactive CD4 thymocytes induce key transcriptional regulators in mTEC and control the composition of mTEC subsets, including Aire mTEC precursors, post-Aire and tuft-like mTECs. Furthermore, these interactions upregulate the expression of tissue-restricted self-antigens, cytokines, chemokines, and adhesion molecules important for T-cell development. This gene activation program induced in mTEC is combined with a global increase of the active H3K4me3 histone mark. Finally, we demonstrate that these self-reactive interactions between CD4 thymocytes and mTECs critically prevent multiorgan autoimmunity. Our genome-wide study thus reveals that self-reactive CD4 thymocytes control multiple unsuspected facets from immature stages of mTECs, which determines their heterogeneity.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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