Zaitseva M B, Mojcik C F, Salomon D R, Shevach E M, Golding H
Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Int Immunol. 1998 Oct;10(10):1551-61. doi: 10.1093/intimm/10.10.1551.
Maturation of thymocytes represents a sequence of events during which thymocytes expressing TCR with moderate avidity for self antigen/MHC are positively selected, whereas those with high or insufficient TCR avidity die. Glucocorticoids are produced intrathymically and can contribute to apoptosis of unselected thymocytes. Thymocytes differentiate in a close contact with epithelial cells, expressing vascular adhesion molecule-1 (VCAM-1) and secreting glucocorticoids, with bone marrow-derived macrophages, and with extracellular matrix containing fibronectin (FN) and collagen. Their contact with FN is mediated by alpha4beta1 and alpha5beta1 integrins. We examined the contribution of TCR and integrin signaling to the survival of thymocytes from dexamethasone (Dex)-induced apoptosis. We demonstrate that FN and VCAM-1 (both of which bind alpha4beta1 integrin), but not collagen, considerably augment TCR-mediated protection of thymocytes from Dex-induced apoptosis. This 'survival' signal is transduced through the alphabeta1, but not through the alpha5beta1 integrin. The observed protection from Dex-induced apoptosis correlated with an increase in bcl-2 protein levels. FN-alpha4beta1 and VCAM-1-alpha4beta1 engagement induced up-regulation bcl-2 protein, while alpha5beta1 binding to FN induced a negative signal that was blocked by anti-alpha5beta1 antibody. These data suggest that alpha4beta1 integrin may contribute to protection of thymocytes with moderate avidity TCR from glucocorticoid-induced death during intrathymic maturation.
胸腺细胞的成熟代表了一系列事件，在此过程中，对自身抗原/MHC具有适度亲和力的表达TCR的胸腺细胞被阳性选择，而那些TCR亲和力高或不足的胸腺细胞则死亡。糖皮质激素在胸腺内产生，可导致未被选择的胸腺细胞凋亡。胸腺细胞与表达血管黏附分子-1（VCAM-1）并分泌糖皮质激素的上皮细胞、骨髓来源的巨噬细胞以及含有纤连蛋白（FN）和胶原蛋白的细胞外基质紧密接触并分化。它们与FN的接触由α4β1和α5β1整合素介导。我们研究了TCR和整合素信号传导对来自地塞米松（Dex）诱导凋亡的胸腺细胞存活的作用。我们证明FN和VCAM-1（两者均结合α4β1整合素），而非胶原蛋白，可以显著增强TCR介导的对胸腺细胞免受Dex诱导凋亡的保护作用。这种“存活”信号通过αβ1而非α5β1整合素转导。观察到的对Dex诱导凋亡的保护作用与bcl-2蛋白水平的增加相关。FN-α4β1和VCAM-1-α4β1的结合诱导bcl-2蛋白上调，而α5β1与FN的结合诱导一种被抗α5β1抗体阻断的负性信号。这些数据表明，α4β1整合素可能有助于在胸腺内成熟过程中保护具有适度亲和力TCR的胸腺细胞免受糖皮质激素诱导的死亡。
