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

Int Immunol. 2011 Nov;23(11):693-700. doi: 10.1093/intimm/dxr076. Epub 2011 Sep 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • CD4 Antigens
  • CD8 Antigens
  • Enzyme Inhibitors
  • Maleimides
  • Receptors, Antigen, T-Cell
  • Tubulin
  • Glycogen Synthase Kinase 3