Deciphering a novel function for TdT in enforcing immunodominace hierarchies of CD8+T lymphocytes

我们将研究一种称为末端脱氧核苷酸转移酶（TdT）的蛋白质在产生抗病毒CD8+ T细胞应答中的作用。CD8+ T细胞是抵抗致病病毒的重要防线。它们识别病毒抗原（即，被免疫系统认为是外来的分子）并转化为能够消除病毒感染细胞的细胞毒性T淋巴细胞（CTL）。众所周知，哺乳动物T细胞库由大量的CTL前体组成，每个前体都带有独特特异性的“预制”抗原受体。T细胞库的多样性是由包括TdT在内的几种关键分子在胸腺中T细胞发育过程中的功能引起的。尽管病毒在宿主细胞内的繁殖产生数千种病毒衍生的肽，并且尽管成年T细胞库含有对许多（如果不是全部）这些肽特异性的CTL前体，但只有有限数量的CTL克隆能够完成检测病毒抗原和对抗病毒入侵者的任务。这几个克隆之间的反应的大小在很大程度上不同，导致它们之间建立一个保守的层次结构。这种现象被称为免疫优势。许多人认为免疫优势是成功的免疫反应靶向尽可能多的抗原位点的障碍。因此，了解免疫优势等级是如何形成的非常重要。虽然已经显示了与宿主细胞内的肽生成维斯的几个因素有助于免疫显性，但是对于胸腺中的早期T细胞发育与在生命后期遇到的病毒应答中诱导的CTL的显性等级之间的关系知之甚少。我们的初步数据表明，TdT作为两个阶段之间缺失的环节发挥了作用。我们将使用现代细胞和分子技术以及多模型系统来揭示TdT在决定病毒特异性T细胞的优势等级中的重要性。这项研究的结果有望促进我们对CD8+ T细胞生物学和免疫优势的理解，并为TdT引入一种新的生物学功能，超越其在T细胞发育过程中的既定作用。

We will investigate the role of a protein called terminal deoxynucleotidyl transferase (TdT) in generation of antiviral CD8+ T cell responses. CD8+ T cells comprise an important line of defense against disease-causing viruses. They recognize viral antigens (i.e., molecules considered by the immune system as foreign) and convert to cytotoxic T lymphocytes (CTLs) capable of eliminating virus-infected cells. It is well known that mammalian T cell repertoire consists of a huge number of CTL precursors, each bearing a "pre-made" antigen receptor of unique specificity. The diversity of T cell repertoire results from the function of several key molecules including TdT during T cell development in the thymus. Although viral propagation inside host cells generates thousands of virus-derived peptides and despite the fact that adult T cell pools contain CTL precursors specific for many (if not all) of these peptides, only a limited number of CTL clones rise to the task of detecting viral antigens and combating viral invaders. The magnitude of responses among these few clones varies to a great extent, leading to the establishment of a conserved hierarchy among them. This phenomenon is called immunodominance. Many consider immunodominance an obstacle to successful immune responses targeting as many antigenic sites as possible. It is therefore important to understand how immunodominance hierarchies are shaped. While several factors vis-à-vis peptide generation within host cells have been shown to contribute to immunodominance, only little is known about the relationship between early T cell development in the thymus and dominance hierarchies of CTLs induced in response to viruses encountered later in life. Our preliminary data point to a role for TdT as a missing link between the two phases. We will use modern cellular and molecular techniques and multiple model systems to reveal the importance of TdT in dictating dominance hierarchies of virus-specific T cells. The findings of this study are expected to advance our understanding of CD8+ T cell biology and immunodominance and to introduce a novel biological function for TdT beyond its well-established role during T cell development.