Journal
NATURE
Volume 559, Issue 7715, Pages 622-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0346-1
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Funding
- Chan Zuckerberg Initiative
- HHMI International Scholar award
- European Research Council Consolidator Grant (ERC-COG) [724471-HemTree2.0]
- Israel Science Foundation [703/15, 1796/16, 722/14]
- Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine
- Helen and Martin Kimmel award for innovative investigation
- Minerva Stiftung
- Israeli Ministry of Science, Technology, and Space
- David and Fela Shapell Family Foundation
- NeuroMac DFG/ Transregional Collaborative Research Center Grant
- Abramson Family Center for Young Scientists
- Sy Syms Foundation
- US-Israel Binational Foundation
- Maurice and Vivienne Wohl Charitable Foundation
- Goodman Family Charitable Lead Annuity Trust
- Ruth and Samuel David Gameroff Family Foundation
- Clore fellowship
- Labex EpiGenMed
- SIRIC Montpellier Cancer Grant [INCa_Inserm_DGOS_12553]
- FRM
- CNRS
- Inserm
- [ERC-2016-CoG-724821]
- [ANR-17-CE15-TUFTEFF]
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T cell development and selection are coordinated in the thymus by a specialized niche of diverse stromal populations(1-3). Although much progress has been made over the years in identifying the functions of the different cell types of the thymic stromal compartment, there is no comprehensive characterization of their diversity and heterogeneity. Here we combined massively parallel single-cell RNA-sequencing(4,5), spatial mapping, chromatin profiling and gene targeting to characterize de novo the entire stromal compartment of the mouse thymus. We identified dozens of cell states, with thymic epithelial cells (TECs) showing the highest degree of heterogeneity. Our analysis highlights four major medullary TEC (mTEC I-IV) populations, with distinct molecular functions, epigenetic landscapes and lineage regulators. Specifically, mTEC IV constitutes a new and highly divergent TEC lineage with molecular characteristics of the gut chemosensory epithelial tuft cells. Mice deficient in Pou2f3, a master regulator of tuft cells, have complete and specific depletion of mTEC IV cells, which results in increased levels of thymus-resident type-2 innate lymphoid cells. Overall, our study provides a comprehensive characterization of the thymic stroma and identifies a new tuft-like TEC population, which is critical for shaping the immune niche in the thymus.
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