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

作者：Cunningham Nicole R; Hinchcliff Emily M; Kutyavin Vassily I; Beck Thomas; Reid Whitney A; Punt Jenni A^*

来源：International Immunology, 2011, 23(11): 693-700.

DOI：10.1093/intimm/dxr076

• GSK3
• MTOC
• TCR
• thymocyte

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.

• 出版日期2011-11