Defining thymic epithelial heterogeneity

描述（由申请人提供）：尽管胸腺环境对于T细胞的产生和有助于定义发育T细胞的自身耐受性的自身投射的重要性，但是产生胸腺上皮的大部分分化程序仍然知之甚少。这方面的一个重要进展是认识到这种上皮细胞是有丝分裂活跃的，并且在出生后不断被替换。这意味着胸腺上皮的组成代表了不同分化阶段上皮细胞的混合物。目前，解析这种上皮异质性的方法是不够的，这阻碍了定义上皮分化程序和将该过程与Aire表达相关的努力，Aire影响胸腺上皮细胞呈递致耐受性自身抗原的能力。我们以前的工作已经证明，Aire-/-胸腺的MTEC隔室表现出与改变的MTEC分化程序一致的特征，其中MTEC亚群的扩增在WT胸腺中是罕见的。我们在这里提出，作为开发试剂抗体的一种手段，从Aire+/+和Aire-/-胸腺产生针对MTEC富集群体的试剂抗体，使我们能够更精确地定义MTEC异质性。这些新的工具将支持我们长期以来的努力，建立胸腺上皮区室内的子代关系，并将有助于努力了解不同的突变，影响胸腺上皮组织影响胸腺上皮分化。 公共卫生相关性：构成胸腺环境的上皮细胞在T细胞的生成和分化中起关键作用。缺乏有关观察到的胸腺上皮异质性的基础知识，阻碍了发展战略，以延缓与年龄相关的胸腺功能丧失或提高胸腺表达的分子，可以调节建立自我耐受的能力。该项目将产生急需的抗体工具，以帮助定义胸腺上皮异质性，并将这些分子的表达与几种受干扰的胸腺上皮分化模型联系起来。

DESCRIPTION (provided by applicant): Despite the importance of the thymic environment for the generation of T cells and the projection of self that helps define self-tolerance for developing T cells, much of the differentiation program that gives rise to thymic epithelium remains poorly understood. An important advance in this area has been the appreciation that this epithelium is mitotically active and that it is continually replaced postnatally. This means that the composition of thymic epithelium represents a mixture of epithelial cells at different stages of differentiation. Presently, the means to parse this epithelial heterogeneity is inadequate and this has hampered efforts to define the program of epithelial differentiation and to relate this process to the expression of Aire, which influences the ability of thymic epithelial cells to present tolerogenic self antigens. Our previous work has demonstrated that the MTEC compartment of the Aire-/- thymus exhibits features consistent with an altered program of MTEC differentiation, with expansion of a MTEC subset that is rare in the WT thymus. We propose here to generate reagent antibodies against enriched populations of MTEC from Aire+/+ and Aire-/- thymi as a means to develop reagent antibodies that will allow us to define MTEC heterogeneity with more precision. These new tools will support our long-standing efforts to establish precursor-progeny relationships within the thymic epithelial compartment and will help efforts to understand how different mutations that affect thymic epithelial organization are affecting thymic epithelial differentiation. PUBLIC HEALTH RELEVANCE: Epithelial cells comprising the thymic environment play a critical role in the generation and differentiation of T cells. Lack of knowledge regarding the basis for the observed heterogeneity of thymic epithelium is impeding the development of strategies to retard age-related loss of thymic function or to enhance thymic expression of molecules that could modulate the ability to establish self-tolerance. This project will generate much needed antibody tools to help define thymic epithelial heterogeneity and relate the expression of these molecules to several models of perturbed thymic epithelial differentiation.