Ongoing Dll4-Notch signaling is required for T-cell homeostasis in the adult thymus
| Autor: | Andrew J. Murphy, Janelle C. Waite, Guoying Chen, Gavin Thurston, Sandra Coetzee, Fabienne Billiard, Kara Olson, Jessica R. Kirshner, Donna Hylton, Amanda DaNave, Dimitris Skokos, Michelle Tait, Sean Taheri, George D. Yancopoulos, Wen Zhang |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Time Factors Stromal cell T-Lymphocytes Immunology Double negative Notch signaling pathway Thymus Gland Biology Antibodies Mice Internal medicine medicine Animals Homeostasis Humans Immunology and Allergy IL-2 receptor Adaptor Proteins Signal Transducing Oligonucleotide Array Sequence Analysis B-Lymphocytes Thymic involution Receptors Notch Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Calcium-Binding Proteins Age Factors Intracellular Signaling Peptides and Proteins Membrane Proteins Cell Differentiation Flow Cytometry Immunohistochemistry Mice Inbred C57BL Thymocyte Endocrinology cardiovascular system Atrophy Signal transduction CD8 Signal Transduction |
| Zdroj: | European Journal of Immunology. 41:2207-2216 |
| ISSN: | 0014-2980 |
| DOI: | 10.1002/eji.201041343 |
| Popis: | The essential role of the Delta-like ligand 4 (Dll4)-Notch signaling pathway in T-lymphocyte development is well established. It has been shown that specific inactivation of Dll4 on thymic stromal cells during early post-natal development leads to a deregulation in T-cell differentiation. However, whether ongoing Dll4-Notch signaling is required for T-cell development in the adult thymus is unknown. The use of anti-Dll4 Abs allowed us to confirm and expand previous studies by examining the kinetics and the reversibility of Dll4-Notch signaling blockade in T-cell development in adult mice. We found that anti-Dll4 treatment reduced thymic cellularity after 7 days, as a consequence of a developmental delay in T-cell maturation at the pro-T-cell double negative 1 (CD4(-) CD8(-) c-kit(+) CD44(+) CD25(-) ) stage, leading to decreased numbers of immature double-positive (CD4(+) CD8(+) ) T cells without affecting the frequency of mature single positive CD4(+) and CD8(+) thymocytes, while promoting alternative thymic B-cell expansion. This cellular phenotype was similarly observed in both young adult and aged mice (>1.5 years), extending our understanding of the ongoing role for Dll4-Notch signaling during T-cell development in the adult thymus. Finally, after cessation of Dll4 Ab treatment, thymic cellularity and thymocyte subset ratios returned to normal levels, indicating reversibility of this phenotype in both adult and aged mice, which has important implications for potential clinical use of Dll4-Notch inhibitors. |
| Databáze: | OpenAIRE |
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