GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+ thymocytes to polarize their MTOC in response to TCR stimulation
| Autor: | Jenni A. Punt, Nicole R. Cunningham, Vassily I. Kutyavin, Whitney A. Reid, Thomas C. Beck, Emily Hinchcliff |
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| Rok vydání: | 2011 |
| Předmět: |
Cellular differentiation
CD8 Antigens T-Lymphocytes Immunology Blotting Western Receptors Antigen T-Cell Biology Aminophenols Lymphocyte Activation Microtubules Polymerization Maleimides Glycogen Synthase Kinase 3 Mice GSK-3 Tubulin Immunology and Allergy Animals Enzyme Inhibitors Thymocytes T-cell receptor Gene Expression Regulation Developmental Microtubule organizing center Cell Differentiation General Medicine T lymphocyte Flow Cytometry Molecular biology Mice Inbred C57BL Thymocyte CD4 Antigens Female Signal transduction Original Research Papers CD8 Microtubule-Organizing Center Signal Transduction |
| Zdroj: | International immunology. 23(11) |
| ISSN: | 1460-2377 |
| Popis: | Although mature T cells divide and differentiate when they receive strong TCR stimulation, most immature CD4+CD8+ thymocytes die. The molecular basis for this marked difference in response is not known. Observations that TCR-stimulated CD4+CD8+ thymocytes fail to polarize their microtubule-organizing center (MTOC), one of the first events that occurs upon antigen activation of mature T cells, suggests that TCR signaling routes in immature and mature T cells diverge early and upstream of MTOC polarization. To better understand the source of the divergence, we examined the molecular basis for the difference in TCR-mediated MTOC polarization. We show that unstable microtubules are a feature of immature murine CD4+CD8+ thymocytes, which also exhibit higher levels of glycogen synthase kinase 3 (GSK3) activity, a known inhibitor of microtubule stability. Importantly, CD4+CD8+ thymocytes gained the ability to polarize their MTOC in response to TCR signals when GSK3 activity was inhibited. GSK3 inhibition also abrogated TCR-mediated apoptosis of immature thymocytes. Together, our results suggest that a developmentally regulated difference in GSK3 activity has a major influence on immature CD4+CD8+ thymocyte versus mature T-cell responses to TCR stimulation. |
| Databáze: | OpenAIRE |
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