| First Author | Lopes N | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 35188458 | Mgi Jnum | J:329063 |
| Mgi Id | MGI:6885178 | Doi | 10.7554/eLife.69982 |
| Citation | Lopes N, et al. (2022) Thymocytes trigger self-antigen-controlling pathways in immature medullary thymic epithelial stages. Elife 11:e69982 |
| abstractText | 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. |
