Gene regulatory logic underlying the differentiation of mixed lineages in human thymic epithelial cells

Authors

Prabakar, R. K., Chapin, S. R., Lin, Y., Staklinski, S. J., Netz, D. M., Lapine, M. E., Pruss, D., Cvetanovic, T., Carcy, S. L., Torres, J., Grosh, A., Kiedrowski, A. J., Pass, H. I., Mosca, R., Regan, C., Preall, J., Siepel, A., Meyer, H. V.

Abstract

The thymus enacts central tolerance through thymic (TECs), which present self-antigens to developing T cells self-reactive cells, preventing autoimmunity. Human TECs include populations that express lineage-committed programs corresponding to distinct peripheral tissues, yet how they acquire these programs and whether these TEC subpopulations are genetically related and conserved in mice remain unknown. Using matched single-cell gene-expression and chromatin-accessibility profiling of 126,687 human TECs, we identified 17 TEC subsets defined by their distinct expression profiles of 1,843 cell type restricted-antigens (CRAs) from 48 peripheral cell types. With a new phylogenetic reconstruction method, we show that lineage-committed TECs share a common ancestor, retain a thymus-specific mixed identity through co-expression of multiple CRA signatures, and are specified by coordinated activator and repressor regulons. We also identified a basement-membrane-collagen-rich state (BMC-TECs) with progenitor-like properties. Finally, mouse TECs shared the regulatory strategy but conserved few master transcription-factor drivers. This study mechanistically characterizes human TEC subpopulations and reveals the gene regulatory logic that leads to their distinct diversification and mixed identities in humans and mice.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 03 Nov 2026.

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