A feedback amplifier circuit with Notch and E2A orchestrates T-cell fate and suppresses the innate lymphoid cell lineages during thymic ontogeny
External signals from the thymic microenvironment and the activities of lineage-specific transcription factors (TFs) instruct T-cell versus innate lymphoid cell (ILC) fates. However, mechanistic insights into how factors such as Notch1-Delta-like-4 (Dll4) signaling and E-protein TFs collaborate to establish T-cell identity remain rudimentary. Using multiple in vivo approaches and single-cell multiome analysis, we identified a feedback amplifier circuit that specifies fetal and adult T-cell fates. In early T progenitors (ETPs) in the fetal thymus, Notch signaling minimally lowered E-protein antagonist <i>Id2</i> levels, and high <i>Id2</i> abundance favored the differentiation of ETPs into ILCs. Conversely, in the adult thymus, Notch signaling markedly decreased <i>Id2</i> abundance in ETPs, substantially elevating E-protein DNA binding and in turn promoting the activation of a T-cell lineage-specific gene expression program linked with V(D)J gene recombination and T-cell receptor signaling. Our findings indicate that, in the fetal versus the adult thymus, a simple feedback amplifier circuit dictated by Notch-mediated signals and <i>Id2</i> abundance enforces T-cell identity and suppresses ILC development.
Authors
- Koichi Ikuta (ORCID: https://orcid.org/0000-0003-1319-1021)
- Kazuko Miyazaki (ORCID: https://orcid.org/0000-0001-9754-698X)
- Rina Hayashi (ORCID: https://orcid.org/0000-0002-0291-9622)
- Risa Karakida Kawaguchi (ORCID: https://orcid.org/0000-0003-1764-5721)
- Kenta Horie (ORCID: https://orcid.org/0000-0003-4175-1014)
- Taishin Akiyama (ORCID: https://orcid.org/0000-0002-0341-6154)
- Kentaro Fujiwara
- Yotaro Ochi (ORCID: https://orcid.org/0000-0001-8472-6164)
- Takuya Uehata (ORCID: https://orcid.org/0000-0003-3517-2198)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Osamu Takeuchi (ORCID: https://orcid.org/0000-0002-1260-6232)
- Katsuto Hozumi (ORCID: https://orcid.org/0000-0002-7685-6927)
- Reiko Hidaka
- Masaki Miyazaki (ORCID: https://orcid.org/0000-0002-9543-624X)
- Gen Kondoh (ORCID: https://orcid.org/0000-0002-2564-0149)
- Georg A. Holländer (ORCID: https://orcid.org/0000-0002-8790-0874)
- Mikihito Takenaka (ORCID: https://orcid.org/0000-0002-6803-048X)
- Norihito Hayatsu
- Hitomi Watanabe (ORCID: https://orcid.org/0000-0001-6448-9966)
- Rei Kuwata
Institutions
- Tokai University (JP)
- University of Basel (CH)
- Kyoto University (JP)
- Board of the Swiss Federal Institutes of Technology (CH)
- University Hospital of Basel (CH)
- Karolinska Institutet (SE)
- Kyoto Medical Center (JP)
- ETH Zurich (CH)
- University of Oxford (GB)
- University Children’s Hospital Basel (CH)
- Regenerative Medicine Institute (MX)
- RIKEN Center for Integrative Medical Sciences (JP)
Publication Details
- Journal
- Genes & Development
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1101/gad.352111.124
- Citations
- 2
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Fujiwara Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Kyoto University Education and Research Foundation
- Astellas Pharma
- Daiichi Sankyo Foundation of Life Science
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Daiichi Sankyo Europe