Thymic development beyond b-selection requires phosphatidylinositol 3-kinase activation by CXCR4
| Autor: | Kristjan S. Gudmundsson, Mamiko Noda, Michelle L. Janas, Takashi Nagasawa, Martin R Turner, Gabriele Varano |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Receptors
CXCR4 T-Lymphocytes T cell Immunology Receptors Antigen T-Cell Beta selection Mammalian embryology Thymus Gland Biology Phosphatidylinositol 3-Kinases Article Cell Line NO Mice chemistry.chemical_compound Catalytic Domain medicine Animals Immunology and Allergy Phosphatidylinositol Receptor Mice Knockout Receptors Notch Kinase Embryo Mammalian Chemokine CXCL12 Cell biology Enzyme Activation medicine.anatomical_structure chemistry Signal transduction Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| Popis: | T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110delta, and class IB, p110gamma catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism behind their functional redundancy in the thymus. Here, we show that PI3K signaling from the preTCR requires p110delta, but not p110gamma. Mice deficient for the class IB regulatory subunit p101 demonstrated the requirement for p101 in T cell development, implicating G protein-coupled receptor signaling in beta-selection. We found evidence of a role for CXCR4 using small molecule antagonists in an in vitro model of beta-selection and demonstrated a requirement for CXCR4 during thymic development in CXCR4-deficient embryos. Finally, we demonstrate that CXCL12, the ligand for CXCR4, allows for Notch-dependent differentiation of DN3 thymocytes in the absence of supporting stromal cells. These findings establish a role for CXCR4-mediated PI3K signaling that, together with signals from Notch and the preTCR, contributes to continued T cell development beyond beta-selection. |
| Databáze: | OpenAIRE |
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