MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood
MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood
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DOI：
10.1093/intimm/dxr073
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发表时间：
2011-10-01
影响因子：
4.4
通讯作者：
Craig, Ruth W.
中科院分区：
文献类型：
--
作者：
Gui, Jingang;Morales, Amanda J.;Craig, Ruth W.
在早期T细胞发育阶段增加细胞库可以增强胸腺生成，当T细胞的产生受到辐射或衰老的影响时尤其有益。在未成熟的双阴性（DN; CD 4（-）CD 8（-））胸腺细胞亚群中，DN 1亚群包含最原始的细胞，包括罕见的早期T细胞祖细胞（ETP）。在本研究中，人MCL 1转基因，在其内源性启动子的控制下，导致C57/BL 6小鼠未变形胸腺的扩大。在1月龄时观察到雌性动物发生胸腺萎缩，但雄性动物未发生，并在胸腺退化至成年期期间维持。小的DN 1亚群被扩增（ETP从胸腺细胞的0.016%增加到0.03%），而更成熟的胸腺细胞沿着基质成比例增加（1.5倍）。来自转基因雌性的DN 1细胞表现出增加的活力，维持增殖，并且它们在原代培养物中的存活时间延长。转基因雌性暴露于γ-辐射也揭示了放射抗性DN 1细胞的扩大池表现出增加的活力。虽然从转基因雄性DN 1细胞的活力是相当于他们的非转基因对应收获后直接，它是在文化中增强，这表明转基因的影响被抑制在体内环境中的男性。从转基因女性的ETP的活力增加，但在更成熟的胸腺细胞不变，表明原始细胞的选择性影响。因此，MCL 1转基因增加了原始ETP/DN 1细胞的活力和池大小，促进了青春期女性和成年女性的胸腺生成和辐射抗性。
Increasing the pool of cells at early T-cell developmental stages enhances thymopoiesis and is especially beneficial when T-cell production is compromised by radiation or aging. Within the immature double-negative (DN; CD4(-)CD8(-)) thymocyte subpopulation, the DN1 subset contains the most primitive cells including the rare early T-cell progenitors (ETPs). In the present study, a human MCL1 transgene, under the control of its endogenous promoter, resulted in enlargement of an undistorted thymus in C57/BL6 mice. Enlargement occurred in females but not males, being seen at 1 month of age and maintained during progression into adulthood as the thymus underwent involution. The small DN1 subset was expanded disproportionally (ETPs increasing from similar to 0.016 to 0.03% of thymocytes), while more mature thymocytes were increased proportionally (1.5-fold) along with the stroma. DN1 cells from transgenic females exhibited increased viability with maintained proliferation, and their survival in primary culture was extended. Exposure of transgenic females to gamma-irradiation also revealed an expanded pool of radioresistant DN1 cells exhibiting increased viability. While the viability of DN1 cells from transgenic males was equivalent to that of their non-transgenic counterparts directly after harvest, it was enhanced in culture-suggesting that the effect of the transgene was suppressed in the in vivo environment of the male. Viability was increased in ETPs from transgenic females, but unchanged in more mature thymocytes, indicating that primitive cells were affected selectively. The MCL1 transgene thus increases the viability and pool size of primitive ETP/DN1 cells, promoting thymopoiesis and radioresistance in peripubescent females and into adulthood.