Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments
Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments
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DOI：
10.1093/intimm/dxf042
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Le, PT
中科院分区：
文献类型：
--
作者：
Ortman, CL;Dittmar, KA;Le, PT
尽管在幼稚T细胞的发育中起着关键作用，但胸腺随着年龄的增长而退化。胸腺退化是由单一的年龄相关缺陷还是多种畸变引起的仍有争议。在这里，我们确定了老化胸腺的胸腺细胞和上皮细胞的分子畸变。我们证明，总胸腺细胞数量下降，逐步动力学，明确的分界线发生在1.5，3，12和22个月的年龄。通过定量PCR，在3个月时首次检测到信号联合TCR切除环（sjTREC）/10（5）胸腺细胞拷贝数减少2.4倍;此后未观察到进一步减少。然而，与1个月相比，胸腺细胞数量和sjTREC/10（5）细胞的联合减少导致sjTREC/胸腺在3个月时减少7倍，在18个月时减少21倍，在22个月时减少72倍。我们发现E2 A表达异常，E2 A是TCR β重排的关键转录调节因子。虽然E2 A表达在3个月时下降了3倍，在7个月时下降了18倍，但E2 A活性的负调节因子LMO 2的表达在18个月时增加了5倍。有趣的是，前Talpha及其转录调节因子HEB的表达并没有随着年龄的增长而减少。此外，角蛋白-8的表达，特异性皮质胸腺上皮细胞，下降3倍，7个月后保持稳定。相比之下，Foxn 1表达在3个月时减少了3倍，在12个月时减少了16倍，在18个月时减少了37倍。IL-7表达直到7个月才减少，到22个月时减少了15倍。因此，这些数据表明，胸腺退化的结果不是从一个单一的缺陷，但最终从一系列的分子畸变在胸腺细胞和胸腺上皮细胞的发展。
Despite playing a critical role in the development of naive T cells, the thymus is involuted with age. Whether a single age-associated defect or multiple aberrations contribute to thymic involution remains controversial. Here, we determined molecular aberrations in the thymocyte and epithelium compartments of the aging thymus. We demonstrated that total thymocyte numbers declined with a stepwise kinetics; clear demarcations occurred at 1.5, 3, 12 and 22 months of age. By quantitative PCR, a 2.4-fold reduction in the copies of signal joint TCR-excised circle (sjTREC)/10(5) thymocytes was first detected at 3 months; no further reduction observed thereafter. Nevertheless, the combined reductions in thymocyte numbers and sjTREC/10(5) cells caused a 7-fold decrease in sjTREC/thymus by 3 months, 21-fold by 18 months and 72-fold by 22 months as compared to 1 month. We showed aberration in expression of E2A, a transcription regulator critical for TCRbeta rearrangement. While E2A expression declined 3-fold by 3 months and 18-fold by 7 months, expression of LMO2, a negative regulator of E2A activities, increased 5-fold by 18 months. Interestingly, expression of pre-Talpha and its transcriptional regulator HEB were not reduced with age. Furthermore, keratin-8 expression, specific for cortical thymic epithelium, declined 3-fold by 7 months and remained stable thereafter. In contrast, Foxn1 expression was reduced 3-fold by 3 months, 16-fold by 12 months and 37-fold by 18 months. IL-7 expression was not reduced until 7 months and reached 15-fold reduction by 22 months. Thus, the data demonstrate that thymic involution results not from a single defect, but culminates from an array of molecular aberrations in both the developing thymocytes and thymic epithelials.