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

我们将研究一种名为末端脱氧核苷酸转移酶(TDT)的蛋白质在产生抗病毒CD8+T细胞反应中的作用。CD8+T细胞是抵御致病病毒的重要防线。它们识别病毒抗原(即免疫系统认为是外来的分子)，并转化为能够清除病毒感染细胞的细胞毒性T淋巴细胞(CTL)。众所周知，哺乳动物的T细胞库由大量的CTL前体组成，每个前体都带有一个具有独特特异性的“预制”抗原受体。T细胞谱系的多样性是胸腺T细胞发育过程中包括TDT在内的几个关键分子作用的结果。尽管病毒在宿主细胞内繁殖产生数以千计的病毒衍生多肽，尽管成人T细胞库含有许多(如果不是全部)这些多肽的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的任务。这几个克隆之间的反应大小差异很大，导致了它们之间建立了保守的等级关系。这种现象被称为免疫优势。许多人认为，免疫优势是以尽可能多的抗原部位为目标的成功免疫反应的障碍。因此，重要的是要了解免疫优势等级是如何形成的。虽然与宿主细胞内的多肽生成相关的几个因素已被证明有助于免疫优势，但对于胸腺早期T细胞发育与随后生命中遇到的病毒诱导的CTL优势等级之间的关系，人们知之甚少。我们的初步数据表明，TDT作为这两个阶段之间缺失的一环发挥了作用。我们将使用现代细胞和分子技术和多模型系统来揭示TDT在决定病毒特异性T细胞的优势等级中的重要性。这项研究的发现有望促进我们对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.