AI Insight
Researchers analyzed 126,687 human thymic epithelial cells (TECs) using single-cell gene expression and chromatin accessibility profiling, identifying 17 distinct TEC subsets that express tissue-specific antigens from 48 different peripheral cell types. They discovered that these specialized TECs share a common ancestor and develop their mixed identities through coordinated activation and repression of specific gene regulatory networks. The study also identified a progenitor-like cell population and revealed that while mice use similar regulatory strategies for TEC differentiation, they employ different master transcription factors, suggesting species-specific mechanisms.
Why it matters
This work provides fundamental insights into how the thymus prevents autoimmune diseases by training T cells to distinguish self from non-self. Understanding the gene regulatory mechanisms controlling TEC diversity could inform therapeutic strategies for treating autoimmune disorders and improving immune system function, particularly in contexts like thymus regeneration or immune reconstitution.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.