ROLE OF IL-7 IN DECREASED THYMOPOIESIS OF AGING

描述：（改编自研究者摘要）随着年龄的增长， 胸腺退化导致T淋巴细胞生成减少。这种减少 从胸腺输出的T细胞被认为对 外周T淋巴细胞区室的组成和功能。先前 这个实验室的工作已经确定了胸腺细胞中的一个年龄敏感步骤 分化过程：最早的前胸腺细胞向T细胞的承诺 细胞谱系，如通过获得CD 25表达所证明的。该步骤 似乎依赖于IL-7。缺乏IL-7或 IL-7 R-α在胸腺生成的这一步骤中显示出特异性阻断，导致 胸腺细胞亚群的分布与老年小鼠非常相似。的 这些基因敲除小鼠与老年小鼠之间亚群分布的相似性 提示，与年龄相关的IL-7信号转导的丢失是一个关键因素， 减少退化胸腺的T细胞产生。三个具体目标 本提案旨在检验这一假设。第一个具体目标是 评估衰老如何影响IL-7信号通路， IL-7的合成，IL-7受体链的数量和分布，以及 早期前胸腺细胞中Jak 1、3和Stat 5的水平和活化 子集第二个具体目标将集中于用以下方法取代IL-7合成： 方法在衰老小鼠胸腺中定向表达，以建立 这种细胞因子合成对T细胞分化的影响。的质粒 含有在可诱导的 四环素启动子已构建，并将用于检测 基质细胞，随后将被移植到胸腺， 中年老鼠第三个目标是确定对T的长期影响 完全绕过IL-7信号传导步骤的淋巴细胞生成 Bcl-2在前胸腺细胞亚群中的表达， 在IL-7-/-和IL-7 R-/-突变体中成功恢复T细胞分化 小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的成年人。

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.