Nonclassical MHC and Early Thymocyte Development

这项提案的总体目标是探索非经典MHC Ib类(Ib类)的参与 胸腺细胞分化中的分子。最近变得更加明显的是，在没有MHC的情况下 1a类(1a类)表达时，胸腺中的Ib类可以选择T细胞。人们对此知之甚少 这种可供选择的胸腺选择过程的生理相关性。我要检验的假设是，在 在发育早期、胸腺分化和T细胞中缺乏(或次优水平)la类分子的表达 细胞教育在很大程度上依赖于班级1b。T细胞的胸腺依赖性及其影响因素 在调节T细胞发育中的关键角色在有颌骨的脊椎动物中被广泛保守。因此， 我建议用非洲爪蛙及其免疫能力强但天然缺乏LA的幼虫阶段作为一种 模型，因为它提供了从外部可以看到幼虫早期发育的胸腺的优点， 易于获取，易于进行实验操作。重要的是，我们的假设涉及Ib类 可以在自然缺乏la类的情况下进行测试，并可以在生物学中研究T细胞的发育 背景。这一建议将提供基本的，而不是系统发生上的限制，对相对的 1a类与1b类介导的胸腺细胞教育途径在个体发育中的作用。

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.