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.

Cunningham NR, Hinchcliff EM, Kutyavin VI, Beck T, Reid WA, Punt JA
Int Immunol. 2011 23 (11): 693-700

PMID: 21937454 · PMCID: PMC3203681 · DOI:10.1093/intimm/dxr076

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.

MeSH Terms (23)

Aminophenols Animals Blotting, Western CD4 Antigens CD8 Antigens Cell Differentiation Enzyme Inhibitors Female Flow Cytometry Gene Expression Regulation, Developmental Glycogen Synthase Kinase 3 Lymphocyte Activation Maleimides Mice Mice, Inbred C57BL Microtubule-Organizing Center Microtubules Polymerization Receptors, Antigen, T-Cell Signal Transduction T-Lymphocytes Thymocytes Tubulin

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