Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.69982
Keywords
thymus; tolerance; medullary thymic epithelial cells; cellular crosstalk; T cells; Mouse
Categories
Funding
- H2020 Marie SklodowskaCurie Actions [CIG_SIGnEPI4Tol_618541]
- Agence Nationale de la Recherche [2011-CHEX-001-R12004KK, ANR-19-CE18-0021-01]
- Agence Nationale de la Recherche (ANR) [ANR-19-CE18-0021] Funding Source: Agence Nationale de la Recherche (ANR)
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Interactions between developing T cells and Aire(+) medullary thymic epithelial cells are crucial for central tolerance induction in the thymus. Self-reactive CD4(+) thymocytes control the transcriptional regulators and composition of mTEC(lo) subsets, including Aire(+) mTEC(hi) precursors, post-Aire and tuft-like mTECs. These interactions upregulate the expression of tissue-restricted self-antigens, cytokines, chemokines, and adhesion molecules important for T-cell development. Our study reveals that self-reactive CD4(+) thymocytes control multiple facets of immature mTECs, determining their heterogeneity.
Interactions of developing T cells with Aire(+) medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEC(hi)) are critical for the induction of central tolerance in the thymus. In turn, thymocytes regulate the cellularity of Aire(+) mTEC(hi). However, it remains unknown whether thymocytes control the precursors of Aire(+) mTEC(hi) that are contained in mTEC(lo) cells or other mTEC(lo) 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(lo) and control the composition of mTEC(lo) subsets, including Aire(+) mTEC(hi) 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(lo) 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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