ROLE OF IL-7 IN DECREASED THYMOPOIESIS OF AGING

描述：(改编自调查人员摘要)随着年龄的增长 胸腺退化导致T淋巴细胞生成减少。这一下降 从胸腺输出的T细胞被认为对 外周T淋巴细胞室的组成和功能。上一首 这个实验室的工作已经在胸腺细胞中发现了一个年龄敏感的步骤。 分化过程：最早的胸腺原细胞对T细胞的承诺 CD25表达的获得证明了细胞的谱系。这一步 似乎依赖于IL-7。IL-7或IL-7缺乏的小鼠 IL-7R-α在胸腺生成的这一步表现出特定的阻断作用，导致 胸腺细胞亚群的分布与老年小鼠的胸腺细胞亚群非常相似。这个 基因敲除小鼠与老龄小鼠亚群分布的相似性 提示与年龄相关的IL-7信号的缺失是导致 退化的胸腺产生的T细胞减少。的三个具体目标 这一提议旨在检验这一假设。第一个具体目标是 通过研究衰老对IL-7信号通路的影响 IL-7的合成，IL-7受体链的数量和分布，以及 早期胸腺原细胞中Jak1、Jak3和Stat 5的水平及活化 子集。第二个具体目标将集中在将IL-7合成替换为 在衰老小鼠胸腺中定向表达的方法，以建立 这种细胞因子合成对T细胞分化的影响。A质粒 含有小鼠IL-7编码区的诱导物 构建了四环素启动子，并将其用于转基因 随后将被移植到小鼠胸腺中的基质细胞 中年老鼠。第三个目标是确定对T的长期影响 构件性完全绕过IL-7信号转导的淋巴细胞生成 BCL-2在胸腺前细胞亚群中的表达，这一方法已经 IL-7-/-和IL-7R-/-突变体成功恢复T细胞分化 老鼠。预计这些研究将导致 增强T淋巴细胞生成从而改善免疫功能的策略 老年人以及其他免疫缺陷成年人。

DESCRIPTION: (adapted from Investigator's abstract) With advancing age the thymus undergoes involution resulting in reduced T lymphopoiesis. This decrease in T cell output from the thymus is thought to have a significant impact on the composition and function of the peripheral T lymphocyte compartment. Previous work from this laboratory has identified an age-sensitive step in the thymocyte differentiation process: the commitment of the earliest pro-thymocyte to the T cell lineage as evidenced by the acquisition of CD25 expression. This step appears to be dependent upon IL-7. Mice which are deficient in either IL-7 or IL-7R-alpha show a specific block at this step of thymopoiesis, resulting in a distribution of thymocyte subsets that greatly resemble those of aged mice. The similarity of subset distribution between these knockout mice and aged mice suggests that an age-related loss of IL-7 signaling is a critical factor in the reduced T cell production of the involuting thymus. The three specific aims of this proposal are designed to test this hypothesis. The first specific aim is to assess how aging impacts the IL-7 signaling pathway by examining the synthesis of IL-7, the quantity and distribution of IL-7 receptor chains, and the levels and activation of Jak 1 and 3 and Stat 5 in early pro-thymocyte subsets. The second specific aim will focus on replacing IL-7 synthesis by means of directed expression in the thymus of aging mice, in order to establish the consequence of such cytokine synthesis on T cell differentiation. A plasmid containing the murine IL-7 coding region under the control of the inducible tetracycline promoter has been constructed and will be used to transfect stromal cells which will subsequently be transplanted into the thymus of middle-aged mice. The third aim is to determine the long-term effect on T lymphopoiesis of completely bypassing the IL-7 signaling step by constitutive Bcl-2 expression in the pro-thymocyte subsets, an approach that has successfully restored T cell differentiation in IL-7-/- and IL-7R-/- mutant mice. It is anticipated that these studies will lead to the development of strategies to enhance T lymphopoiesis and thereby improve immune function in the elderly as well as other immunodeficient adults.