Lymphoid signals for stromal growth and organization in the thymus.

描述（由申请人提供）：与所有血细胞一样，T 淋巴细胞在生命过程中不断丢失，必须不断补充。胸腺是 T 淋巴细胞从头生成的主要部位。胸腺特有的微环境条件诱导多能、骨髓来源的祖细胞发生一系列复杂的发育事件，包括增殖的阳性和阴性控制、T谱系规范、功能性T谱系不对称、自我限制、自我耐受和细胞死亡/生存信号。在理解胸腺向淋巴祖细胞提供的信号以诱导和控制这些事件方面已经取得了重大进展。然而，胸腺非淋巴（基质）成分的增殖、分化和/或存活同样依赖于淋巴样细胞，并且淋巴样细胞的缺乏（例如先天性免疫缺陷疾病）会导致无胸腺，即使新生基质细胞具有功能能力。淋巴样细胞提供的诱导基质生长、分化和/或存活的信号是完全未知的。在本提案中，我们建议以全面的方式解决这一过程。使用我们最近设计的原位基质基因表达的整体表征方法，我们将分析基质细胞对胸腺生长诱导模型中淋巴祖细胞存在的动态反应。然后，我们将鉴定编码受体的基质表达基因，从而可能对淋巴细胞的存在做出反应，特别强调那些在生长反应的特定阶段（诱导、对数期、终止、稳态）发生变化的基因。我们将使用信息方法以及手动管理方法来验证淋巴细胞中这些受体的同源配体的存在。然后，将使用各种标准对同源受体：配体对进行优先级排序，包括动态表达模式、其他组织中已知的功能相关性（生长、分化、存活）、现有遗传模型的可用性等。最后，将使用适当的基质受体或淋巴配体突变小鼠模型来测试一些高优先级候选物的生物学相关性。该项目预计将为未探索的生物学领域提供新颖的见解，不仅有助于更好地理解这一过程，而且将促进更多机制研究的发展，以表征胸腺中淋巴祖细胞和基质细胞之间发生的独特的双向相互作用。 公众健康相关性：胸腺是产生 T 淋巴细胞的主要器官，因此对于正常免疫功能至关重要。胸腺内的特殊细胞（基质细胞）负责指示从骨髓中招募的干细胞样细胞发育成 T 淋巴细胞。然而，在发育早期，这些基质细胞本身需要来自未成熟淋巴细胞的信号来诱导其自身的生长和发育。例如，在缺乏淋巴细胞的情况下，如许多儿科免疫缺陷疾病中所发生的那样，胸腺就不会形成。该项目的目标是深入分析胸腺中淋巴细胞和基质细胞之间的双向相互作用，以及这些过程如何影响免疫系统的发育。

DESCRIPTION (provided by applicant): Like all blood cells, T lymphocytes are constantly lost during life, and must be continuously replaced. The thymus is the primary site of de novo T lymphopoiesis. Microenvironmental conditions unique to the thymus induce a complex series of developmental events in multipotent, marrow-derived progenitors, including positive and negative control of proliferation, T lineage specification, functional T lineage asymmetry, self-restriction, self-tolerance, and cell death/survival signals. Significant progress has been made in understanding the signals the thymus provides to lymphoid progenitors to induce and control these events. However, the proliferation, differentiation, and/or survival of the non-lymphoid (stromal) components of the thymus are equally dependent on lymphoid cells, and the absence of lymphoid cells (e.g., congenital immunodeficiency diseases) results in athymia, even though the nascent stromal cells are functionally competent. The signals that lymphoid cells provide to induce stromal growth, differentiation, and/or survival are completely unknown. In this proposal, we propose to address this process in a comprehensive fashion. Using our recently devised method for global characterization of stromal gene expression in situ, we will analyze the dynamic response of stromal cells to the presence of lymphoid progenitors in an inducible model of thymic growth. We will then identify stromally-expressed genes that encode receptors, and thus may respond to the presence of lymphoid cells, with particular emphasis on those that change during specific phases of the growth response (induction, log phase, termination, steady-state). We will verify the presence of the cognate ligands for these receptors in lymphoid cells, using informatic methods as well as manual means of curation. Cognate receptor:ligand pairs will then be prioritized using a variety of criteria, including dynamic patterns of expression, known functional relevance (growth, differentiation, survival) in other tissues, the availability of existing genetic models, etc. Finally, the biological relevance of a few high-priority candidates will be tested, using appropriate stromal- receptor or lymphoid-ligand mutant mouse models. This project is expected to provide novel insights into an unexplored area of biology that will not only fuel a better understanding of this process, but will facilitate the development of more mechanistic studies to characterize the unique, two-way interactions that occur between lymphoid progenitors and stromal cells in the thymus. PUBLIC HEALTH RELEVANCE: The thymus is the primary organ where T lymphocytes are made, and thus is critical for normal immune function. Specialized cells inside the thymus (stromal cells) are responsible for instructing stem-like cells recruited from the bone marrow to undergo development into T lymphocytes. However, early in development, these stromal cells themselves require signals from immature lymphocytes to induce their own growth and development. In the absence of lymphocytes, for instance, as occurs in many pediatric immunodeficiency disorders, the thymus does not form. The goals of this project are to perform an in depth analysis of this very poorly understood two-way interplay between lymphocytes and stromal cells in the thymus, and how these processes shape the development of the immune system.