Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, D-79108 Freiburg, Germany.
Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3463-8. doi: 10.1073/pnas.1118823109. Epub 2012 Feb 13.
Involution of the thymus is accompanied by a decline in the number of thymic epithelial cells (TECs) and a severely restricted peripheral repertoire of T-cell specificities. TECs are essential for T-cell differentiation; they originate from a bipotent progenitor that gives rise to cells of cortical (cTEC) and medullary (mTEC) phenotypes, via compartment-specific progenitors. Upon acute selective near-total ablation during embryogenesis, regeneration of TECs fails, suggesting that losses from the pool of TEC progenitors are not compensated. However, it is unclear whether this is also true for the compartment-specific progenitors. The decline of cTECs is a prominent feature of thymic involution. Because cTECs support early stages of T-cell development and hence determine the overall lymphopoietic capacity of the thymus, it is possible that the lack of sustained regenerative capacity of cTEC progenitor cells underlies the process of thymic involution. Here, we examine this hypothesis by cell-type-specific conditional ablation of cTECs. Expression of the human diphtheria toxin receptor (hDTR) gene under the regulatory influence of the chemokine receptor Ccx-ckr1 gene renders cTECs sensitive to the cytotoxic effects of diphtheria toxin (DT). As expected, DT treatment of preadolescent and adult mice led to a dramatic loss of cTECs, accompanied by a rapid demise of immature thymocytes. Unexpectedly, however, the cTEC compartment regenerated after cessation of treatment, accompanied by the restoration of T-cell development. These findings provide the basis for the development of targeted interventions unlocking the latent regenerative potential of cTECs to counter thymic involution.
胸腺的退化伴随着胸腺上皮细胞（TEC）数量的减少和 T 细胞特异性的外周库严重受限。TEC 对于 T 细胞分化至关重要；它们起源于一个双能祖细胞，通过特定于隔室的祖细胞产生皮质（cTEC）和髓质（mTEC）表型的细胞。在胚胎发生期间急性选择性近乎完全消融时，TEC 的再生失败，这表明 TEC 祖细胞库中的损失没有得到补偿。然而，对于特定于隔室的祖细胞是否也是如此尚不清楚。cTEC 的减少是胸腺退化的一个突出特征。由于 cTEC 支持 T 细胞发育的早期阶段，因此决定了胸腺的整体淋巴生成能力，因此，cTEC 祖细胞缺乏持续的再生能力可能是胸腺退化的过程的基础。在这里，我们通过 cTEC 的细胞类型特异性条件性消融来检验这一假说。趋化因子受体 Ccx-ckr1 基因调控下的人白喉毒素受体（hDTR）基因的表达使 cTEC 对白喉毒素（DT）的细胞毒性作用敏感。正如预期的那样，DT 处理青春期前和成年小鼠导致 cTEC 的急剧丧失，伴随着不成熟的胸腺细胞的迅速死亡。然而，出乎意料的是，cTEC 隔室在停止治疗后再生，伴随着 T 细胞发育的恢复。这些发现为开发靶向干预措施提供了基础，这些干预措施可以释放 cTEC 的潜在再生潜力，以对抗胸腺退化。
