Nonclassical MHC and Early Thymocyte Development

描述（由申请人提供）：本提案的总体目标是探索非经典MHC Ib类（Ib类）分子参与胸腺细胞分化。最近变得更加明显的是，在没有MHC Ia类（Ia类）表达的情况下，T细胞可以在胸腺中被Ib类选择。关于这种替代性胸腺选择过程的生理相关性，我们知之甚少。假设我的目的是测试的是，在缺乏（或次优水平）的类Ia表达的早期发展，胸腺分化和T细胞教育严重依赖于Ib类。T细胞的胸腺依赖性和在调节T细胞发育中起关键作用的因子在有颌脊椎动物中广泛保守。因此，我建议使用蛙爪蟾和它的免疫活性，但自然类Ia缺陷的幼虫阶段，作为一个模型，因为它提供了具有早期发育胸腺的幼虫外部可见，易于访问和服从实验操作的优势。重要的是，我们涉及Ib类的假设可以在天然缺乏Ia类的情况下进行测试，并且可以在生物学背景下研究T细胞的发育。这个建议将提供基本的，而不是遗传学限制，洞察类Ia与类Ib介导的胸腺细胞教育途径在个体发育过程中的相对贡献。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to explore the involvement of non-classical MHC class Ib (class Ib) molecules in thymocyte differentiation. It has recently become more evident that in the absence of MHC class la (class la) expression, T cells can be selected by class Ib in the thymus. Not much is known about the physiological relevance of this alternative thymic selection process. The hypothesis I aim to test is that in the absence (or suboptimal level) of class la expression early in development, thymic differentiation and T cell education critically depends on class Ib. Both the thymic dependence of T cells and the factors that play key roles in the regulation of T cell development are broadly conserved among jawed vertebrates. Therefore, I propose to use the frog Xenopus and its immunocompetent but naturally class la-deficient larval stage, as a model because it provides the advantage of having the early developing thymus of larvae externally visible, easily accessible and amenable to experimental manipulation. Importantly, our hypothesis involving class Ib can be tested in the natural absence of class la and the development of T cells can be studied in a biological context. This proposal will provide fundamental, and not phylogenetically restricted, insight on the relative contributions of class la versus class Ib-mediated thymocyte education pathways during ontogeny.