Thymic mimetic cells function beyond self-tolerance

Tal Givony, Dena Leshkowitz, Diana Castillo, Shir Nevo, Noam Kadouri, Bareket Dassa, Yael Gruper, Razi Khalaila, Osher Ben-Nun, Tom Gome, Jan Dobeš, Shifra Ben-Dor, Merav Kedmi, Hadas Keren-Shaul, Rebecca Heffner-Krausz, Ziv Porat, Ofra Golani, Yoseph Addadi, Ori Brenner, David D. Lo, Yael Goldfarb () and Jakub Abramson ()
Additional contact information
Tal Givony: Weizmann Institute of Science
Dena Leshkowitz: Weizmann Institute of Science
Diana Castillo: University of California, Riverside
Shir Nevo: Weizmann Institute of Science
Noam Kadouri: Weizmann Institute of Science
Bareket Dassa: Weizmann Institute of Science
Yael Gruper: Weizmann Institute of Science
Razi Khalaila: Weizmann Institute of Science
Osher Ben-Nun: Weizmann Institute of Science
Tom Gome: Weizmann Institute of Science
Jan Dobeš: Weizmann Institute of Science
Shifra Ben-Dor: Weizmann Institute of Science
Merav Kedmi: Weizmann Institute of Science
Hadas Keren-Shaul: Weizmann Institute of Science
Rebecca Heffner-Krausz: Weizmann Institute of Science
Ziv Porat: Weizmann Institute of Science
Ofra Golani: Weizmann Institute of Science
Yoseph Addadi: Weizmann Institute of Science
Ori Brenner: Weizmann Institute of Science
David D. Lo: University of California, Riverside
Yael Goldfarb: Weizmann Institute of Science
Jakub Abramson: Weizmann Institute of Science

Nature, 2023, vol. 622, issue 7981, 164-172

Abstract: Abstract Development of immunocompetent T cells in the thymus is required for effective defence against all types of pathogens, including viruses, bacteria and fungi. To this end, T cells undergo a very strict educational program in the thymus, during which both non-functional and self-reactive T cell clones are eliminated by means of positive and negative selection1.Thymic epithelial cells (TECs) have an indispensable role in these processes, and previous studies have shown the notable heterogeneity of these cells2–7. Here, using multiomic analysis, we provide further insights into the functional and developmental diversity of TECs in mice, and reveal a detailed atlas of the TEC compartment according to cell transcriptional states and chromatin landscapes. Our analysis highlights unconventional TEC subsets that are similar to functionally well-defined parenchymal populations, including endocrine cells, microfold cells and myocytes. By focusing on the endocrine and microfold TEC populations, we show that endocrine TECs require Insm1 for their development and are crucial to maintaining thymus cellularity in a ghrelin-dependent manner; by contrast, microfold TECs require Spib for their development and are essential for the generation of thymic IgA+ plasma cells. Collectively, our study reveals that medullary TECs have the potential to differentiate into various types of molecularly distinct and functionally defined cells, which not only contribute to the induction of central tolerance, but also regulate the homeostasis of other thymus-resident populations.

Date: 2023
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DOI: 10.1038/s41586-023-06512-8

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