Thymic selection of MAIT cells

T细胞构成了适应性免疫系统的核心部分。此外，某些T细胞群，通常被称为非常规T细胞，存在共享先天性和适应性免疫两者的功能谱。粘膜相关的不变T（MAIT）细胞是这组T细胞的一部分。它们在各种人体组织中构成了非常丰富的群体，占所有血液T细胞的近10%和所有肝脏T细胞的20-40%。MAIT细胞表达半变体T细胞受体（TCR）并识别维生素B代谢物。与它们的先天性一样，它们也能够直接响应细胞因子的刺激。与人类相比，MAIT细胞在小鼠中非常罕见。因此，对MAIT细胞功能的理解，以及它们的发展，仍然处于起步阶段。MAIT细胞与不变的自然杀伤T细胞共享一些特征，但也存在一些显着差异。我们的实验室最近证明，MAIT细胞的发育关键取决于一个单一的miRNA，miR-181 a/B-1。在这里，我们建议研究MAIT细胞的发育，以回答基本的开放性问题：1）MAIT细胞，像其他非常规T细胞一样，在发育过程中依赖于强TCR信号吗？2)在胸腺发育过程中，MAIT细胞的代谢要求是什么？3)什么额外的分子机制，如生存信号，是胸腺中MAIT细胞发育的关键？为了解决这些问题，我们将利用遗传工具，包括揭示细胞发育年龄的分子计时器，以及最近产生的MAIT细胞丰度增加的小鼠品系。总之，提出的实验将大大增加我们对MAIT细胞在胸腺中产生的分子机制的理解。因此，这些研究将促进我们对MAIT细胞生物学的总体理解，并可能有助于更好地了解MAIT细胞在免疫应答过程中的作用。

T cells constitute a central part of the adaptive immune system. In addition, certain T cell populations, frequently referred to as unconventional T cells, exist that share functional profiles of both, innate and adaptive immunity. Mucosal-associated Invariant T (MAIT) cells are part of this group of T cells. They constitute a very abundant population in various human tissues, comprising almost 10% of all blood T cells and 20-40% of all liver T cells. MAIT cells express a semi-variant T cell receptor (TCR) and recognize vitamin B metabolites. In keeping with their innate-like nature they are also able to directly respond to stimulation by cytokines. In contrast to humans, MAIT cells are exceedingly rare in mice. Therefore, the understanding of MAIT cell function and, even more so, their development, remain in its infancy. MAIT cells share some characteristics with invariant natural killer T cells, but some notable differences exist as well. Our laboratory has recently demonstrated that MAIT cell development critically depends on a single miRNA, miR-181a/b-1. Here, we propose to study MAIT cell development to answer fundamental open questions: 1) Do MAIT cells, like other unconventional T cells, depend on strong TCR signals during development? 2) What are the metabolic requirements of MAIT cells during development in the thymus? 3) What additional molecular mechanisms, such as survival signals, are key to MAIT cell development in the thymus? To address these questions, we will take advantage of genetic tools including a molecular timer revealing a cell’s developmental age as well as a recently generated mouse strain with increased abundance of MAIT cells. Together, the experiments proposed will substantially add to our understanding of the molecular mechanisms underlying MAIT cell generation in the thymus. These studies will therefore foster our understanding of MAIT cell biology in general and may help to better understand the role of MAIT cells during an immune response.