Notch1 and IL-7 Receptor Interplay Maintains Proliferation of Human Thymic Progenitors while Suppressing Non-T Cell Fates
| العنوان: | Notch1 and IL-7 Receptor Interplay Maintains Proliferation of Human Thymic Progenitors while Suppressing Non-T Cell Fates |
|---|---|
| المؤلفون: | Marina García-Peydró, María L. Toribio, Virginia G. de Yébenes |
| المساهمون: | Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Fundación 'la Caixa', Fundación Eugenio Rodríguez Pascual, Fundación Ramón Areces |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| بيانات النشر: | The American Association of Immunologists, 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Stromal cell, T-Lymphocytes, Cellular differentiation, T cell, Immunology, T cells, Notch signaling pathway, Thymus Gland, Biology, Cell Line, Mice, Organ Culture Techniques, medicine, Animals, Humans, Immunology and Allergy, Receptor, Notch1, Progenitor cell, Cells, Cultured, Myeloid Progenitor Cells, Cell proliferation, Cell Proliferation, Receptors, Interleukin-7, Cell growth, Infant, Newborn, Infant, Growth Inhibitors, Hematopoiesis, Thymus, Cell biology, Proto-Oncogene Proteins c-kit, Haematopoiesis, medicine.anatomical_structure, fms-Like Tyrosine Kinase 3, Cell culture, Child, Preschool, Signal Transduction, Human |
| الوصف: | Article available at http://www.jimmunol.org/cgi/content/abstract/177/6/3711Test Notch signaling is critical for T cell development of multipotent hemopoietic progenitors. Yet, how Notch regulates T cell fate specification during early thymopoiesis remains unclear. In this study, we have identified an early subset of CD34highc-kit+flt3+IL-7R+ cells in the human postnatal thymus, which includes primitive progenitors with combined lymphomyeloid potential. To assess the impact of Notch signaling in early T cell development, we expressed constitutively active Notch1 in such thymic lymphomyeloid precursors (TLMPs), or triggered their endogenous Notch pathway in the OP9-Delta-like1 stroma coculture. Our results show that proliferation vs differentiation is a critical decision influenced by Notch at the TLMP stage. We found that Notch signaling plays a prominent role in inhibiting non-T cell differentiation (i.e., macrophages, dendritic cells, and NK cells) of TLMPs, while sustaining the proliferation of undifferentiated thymocytes with T cell potential in response to unique IL-7 signals. However, Notch activation is not sufficient for inducing T-lineage progression of proliferating progenitors. Rather, stroma-derived signals are concurrently required. Moreover, while ectopic IL-7R expression cannot replace Notch for the maintenance and expansion of undifferentiated thymocytes, Notch signals sustain IL-7R expression in proliferating thymocytes and induce IL-7R up-regulation in a T cell line. Thus, IL-7R and Notch pathways cooperate to synchronize cell proliferation and suppression of non-T lineage choices in primitive intrathymic progenitors, which will be allowed to progress along the T cell pathway only upon interaction with an inductive stromal microenvironment. These data provide insight into a mechanism of Notch-regulated amplification of the intrathymic pool of early human T cell progenitors This work was supported by grants from Plan Nacional de Biomedicina (SAF2004-01122 and GEN2003-20649-C06-02), Comunidad de Madrid (GR/SAL/0143/ 2004), Fundación La Caixa (ON03/109-00), and Fundación Eugenio Rodríguez Pascual. We thank the Fundación Ramón Areces for an institutional grant to the Centro de Biología Molecular Severo Ochoa |
| وصف الملف: | 664838 bytes; application/pdf |
| تدمد: | 1550-6606 0022-1767 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2b2e1b163b96086fde31ab5f8f864fb9Test https://doi.org/10.4049/jimmunol.177.6.3711Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2b2e1b163b96086fde31ab5f8f864fb9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
|---|