Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis
| Autor: | David A. Hildeman, Pulak Tripathi, Fukun Guo, H. Leighton Grimes, Chinavenmeni S. Velu, Yi Zheng |
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| Rok vydání: | 2010 |
| Předmět: |
MAP Kinase Signaling System
T-Lymphocytes medicine.medical_treatment Cellular differentiation Receptors Antigen T-Cell Gene Expression Mice Transgenic CDC42 Biology Lymphocyte Activation Mice medicine Animals Homeostasis cdc42 GTP-Binding Protein Receptor Transcription factor Cell Proliferation DNA Primers Mice Knockout Receptors Interleukin-7 Multidisciplinary Base Sequence Cell growth T-cell receptor Cell Differentiation Biological Sciences Recombinant Proteins Cell biology DNA-Binding Proteins Cytokine p21-Activated Kinases Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:18505-18510 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1010249107 |
| Popis: | T-cell homeostasis is essential for normal functioning of the immune system. IL-7 receptor (IL-7R) and T-cell receptor (TCR) signaling are pivotal for T-cell homeostatic regulation. The detailed mechanisms regulating T-cell homeostasis and how IL-7R and TCR signaling are coordinated are largely unknown. Here we demonstrate that T cell-specific deletion of cell-division cycle 42 ( Cdc42 ) GTPase causes a profound loss of mature T cells. Deletion of Cdc42 leads to a markedly increased expression of growth factor independence-1 (Gfi-1) and represses expression of IL-7Rα. In the absence of Cdc42 , aberrant ERK1/2 MAP kinase activity results in enhanced, TCR-mediated T-cell proliferation. In vivo reconstitution of effector-binding–defective Cdc42 mutants and the effector p21 protein-activated kinase 1 (PAK1) into Cdc42 -deficient T cells showed that PAK1 is both necessary and sufficient for Cdc42-regulated T-cell homeostasis. Thus, T-cell homeostasis is maintained through a concerted regulation of Gfi-1–IL-7R–controlled cytokine responsiveness and ERK-mediated TCR signaling strength by the Cdc42-PAK1 signaling axis. |
| Databáze: | OpenAIRE |
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