Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells

Chamutal Bornstein, Shir Nevo, Amir Giladi, Noam Kadouri, Marie Pouzolles, François Gerbe, Eyal David, Alice Machado, Anna Chuprin, Beáta Tóth, Ori Goldberg, Shalev Itzkovitz, Naomi Taylor, Philippe Jay, Valérie S. Zimmermann, Jakub Abramson () and Ido Amit ()
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Chamutal Bornstein: Weizmann Institute of Science
Shir Nevo: Weizmann Institute of Science
Amir Giladi: Weizmann Institute of Science
Noam Kadouri: Weizmann Institute of Science
Marie Pouzolles: University of Montpellier, CNRS
François Gerbe: University of Montpellier
Eyal David: Weizmann Institute of Science
Alice Machado: University of Montpellier, CNRS
Anna Chuprin: Weizmann Institute of Science
Beáta Tóth: Weizmann Institute of Science
Ori Goldberg: Schneider Children’s Medical Center
Shalev Itzkovitz: Weizmann Institute of Science
Naomi Taylor: University of Montpellier, CNRS
Philippe Jay: University of Montpellier
Valérie S. Zimmermann: University of Montpellier, CNRS
Jakub Abramson: Weizmann Institute of Science
Ido Amit: Weizmann Institute of Science

Nature, 2018, vol. 559, issue 7715, 622-626

Abstract: Abstract T cell development and selection are coordinated in the thymus by a specialized niche of diverse stromal populations1–3. 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-sequencing4,5, 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.

Date: 2018
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DOI: 10.1038/s41586-018-0346-1

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