| First Author | Cunningham NR | Year | 2011 |
| Journal | Int Immunol | Volume | 23 |
| Issue | 11 | Pages | 693-700 |
| PubMed ID | 21937454 | Mgi Jnum | J:177280 |
| Mgi Id | MGI:5294694 | Doi | 10.1093/intimm/dxr076 |
| Citation | Cunningham NR, et al. (2011) 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 23(11):693-700 |
| abstractText | 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. |
