| First Author | Michelson DA | Year | 2022 |
| Journal | Cell | Volume | 185 |
| Issue | 14 | Pages | 2542-2558.e18 |
| PubMed ID | 35714609 | Mgi Jnum | J:353736 |
| Mgi Id | MGI:7314058 | Doi | 10.1016/j.cell.2022.05.018 |
| Citation | Michelson DA, et al. (2022) Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. Cell 185(14):2542-2558.e18 |
| abstractText | Medullary thymic epithelial cells (mTECs) ectopically express thousands of peripheral-tissue antigens (PTAs), which drive deletion or phenotypic diversion of self-reactive immature T cells during thymic differentiation. Failure of PTA expression causes multiorgan autoimmunity. By assaying chromatin accessibility in individual mTECs, we uncovered signatures of lineage-defining transcription factors (TFs) for skin, lung, liver, and intestinal cells-including Grhl, FoxA, FoxJ1, Hnf4, Sox8, and SpiB-in distinct mTEC subtypes. Transcriptomic and histologic analyses showed that these subtypes, which we collectively term mimetic cells, expressed PTAs in a biologically logical fashion, mirroring extra-thymic cell types while maintaining mTEC identity. Lineage-defining TFs bound to mimetic-cell open chromatin regions and were required for mimetic cell accumulation, whereas the tolerogenic factor Aire was partially and variably required. Expression of a model antigen in mimetic cells sufficed to induce cognate T cell tolerance. Thus, mTECs co-opt lineage-defining TFs to drive mimetic cell accumulation, PTA expression, and self-tolerance. |
