Ashwell J D, King L B, Vacchio M S
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, USA.
Stem Cells. 1996 Sep;14(5):490-500. doi: 10.1002/stem.140490.
The fate of an immature thymocyte, life or death, is largely determined by the ligand-specificity of its T cell antigen receptor (TCR). The default pathway for thymocytes bearing TCRs with subthreshold avidity for self-antigens is death (death by neglect). Thymocytes bearing TCRs with high avidity for self also undergo apoptosis (negative selection). Those thymocytes with intermediate avidities, or that perhaps recognize self-peptides that have partial agonist or antagonist properties, survive and differentiate into mature immunocompetent T cells (positive selection). How TCR avidity is interpreted as a "rescue" signal or a death signal is unknown. Based upon a T cell hybridoma model, our laboratory proposed that glucocorticoids, which themselves are potent inducers of thymocyte apoptosis, antagonize TCR-mediated thymocyte deletion and allow positive selection to occur. In fact, epithelial cells in the thymus proved to be a source of steroid production, and interference with steroid synthesis in fetal thymic organ culture resulted in a greatly enhanced sensitivity of thymocytes to TCR-mediated apoptosis. Transgenic mice with reduced glucocorticoid receptor (GR) levels were produced by tissue-specific expression of GR antisense. Thymocytes in these mice had high levels of spontaneous apoptosis, and were exquisitely sensitive to deletion induced by cross-linking the TCR. Moreover, there was a very large (> or = 90%) loss of CD4+CD8+ thymocytes, signifying a block at the CD4-CD8- to CD4+CD8+ transition, perhaps due to apoptosis of cells upon engagement of the pre-TCR in the absence of an antagonizing glucocorticoid stimulus. The molecular mechanism of the antagonism is currently being investigated. These data indicate that there is cross-talk in thymocytes between the TCR and glucocorticoid signaling pathways resulting in apoptosis, and that locally produced steroids, in a paracrine fashion, participate in setting the TCR avidity thresholds that determine whether developing thymocytes survive or die, and therefore help to mold the antigen-specific T cell repertoire.
未成熟胸腺细胞的命运，是生还是死，很大程度上由其T细胞抗原受体（TCR）的配体特异性决定。对于自身抗原亲和力低于阈值的TCR的胸腺细胞，其默认途径是死亡（被忽视的死亡）。对自身具有高亲和力的TCR的胸腺细胞也会经历凋亡（阴性选择）。那些具有中等亲和力的胸腺细胞，或者可能识别具有部分激动剂或拮抗剂特性的自身肽的胸腺细胞，会存活并分化为成熟的具有免疫能力的T细胞（阳性选择）。TCR亲和力如何被解读为“拯救”信号或死亡信号尚不清楚。基于T细胞杂交瘤模型，我们实验室提出，糖皮质激素本身是胸腺细胞凋亡的强效诱导剂，它拮抗TCR介导的胸腺细胞缺失并允许阳性选择发生。事实上，胸腺中的上皮细胞被证明是类固醇产生的来源，在胎儿胸腺器官培养中干扰类固醇合成会导致胸腺细胞对TCR介导的凋亡的敏感性大大增强。通过糖皮质激素受体（GR）反义RNA的组织特异性表达产生了GR水平降低的转基因小鼠。这些小鼠中的胸腺细胞具有高水平的自发凋亡，并且对TCR交联诱导的缺失极为敏感。此外，CD4+CD8+胸腺细胞有非常大（≥90%）的损失，这表明在CD4-CD8-到CD4+CD8+转变阶段出现阻滞，这可能是由于在没有拮抗糖皮质激素刺激的情况下，前TCR结合后细胞发生凋亡所致。目前正在研究这种拮抗作用的分子机制。这些数据表明，在胸腺细胞中，TCR和糖皮质激素信号通路之间存在导致凋亡产生的相互作用，并且局部产生的类固醇以旁分泌方式参与设定TCR亲和力阈值，该阈值决定发育中的胸腺细胞是存活还是死亡，因此有助于塑造抗原特异性T细胞库。
