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。最近发现，在缺乏MHC la类(la类)表达的情况下，胸腺中的T细胞可以被Ib类所选择。关于这一替代胸腺选择过程的生理相关性，人们知之甚少。我想要检验的假设是，在发育早期缺乏(或次优水平)1a类基因表达的情况下，胸腺分化和T细胞教育严重依赖ib类基因。在颌骨脊椎动物中，T细胞的胸腺依赖性和在调节T细胞发育中发挥关键作用的因子都被广泛保守。因此，我建议使用非洲爪蛙和它的免疫活性但自然缺乏LA类幼虫阶段作为模型，因为它提供的优势是，早期发育的幼虫胸腺在外部可见，很容易接触到，并易于实验操作。重要的是，我们关于Ib类的假设可以在自然不存在1a类的情况下得到检验，而T细胞的发育可以在生物学背景下进行研究。这一建议将提供基本的、不受系统发育限制的洞察力，了解在个体发育过程中，1a类与1b类介导的胸腺细胞教育途径的相对贡献。

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.