The regulation and functions of Group 1 CD1-restricted T cells

项目摘要 第1组CD 1限制性T细胞是非常规T细胞家族的成员，其识别自身免疫细胞和非免疫细胞。 由CD 1a、CD 1b和CD 1c分子呈递的微生物脂质抗原。第1组CD 1限制性T细胞 在各种自身免疫性疾病和感染性疾病中发挥着关键作用， 结核分枝杆菌（Mtb）感染。虽然第1组CD 1-限制性T细胞代表了大量的 人类T细胞库的一部分，进一步了解它们在体内的功能和调节， 免疫应答因小鼠中缺乏组1CD 1表达而受阻。我们先前已经 产生了具有完整的人组1 CD 1基因座（hCD 1 Tg）和TCR的转基因小鼠模型 具有Mtb脂质和自身脂质特异性的转基因小鼠模型。我们证明了分枝菌酸 （MA）特异性和自身脂质特异性CD 1b限制性T细胞赋予针对Mtb感染的保护。在 此外，CD 1b自身反应性T细胞的慢性激活可导致银屑病样皮肤的发展 ApoE缺陷型高脂血症小鼠模型中的炎症。由于高脂血症是一种常见的疾病， 在艾滋病毒感染者和一般人群中，我们的目标是进一步了解它如何影响 使用Mtb感染作为模型，在感染期间第1组CD 1限制性T细胞的功能。在目标1中，TCR 将使用hCD 1 Tg/LDLR-/-背景中的转基因小鼠模型来确定饮食- 诱导高脂血症的自身和微生物的脂质特异性T细胞，并阐明分子和细胞 机制介导这种效应。高脂血症对多克隆组1 CD 1-限制性T细胞的影响 对Mtb感染的细胞应答也将通过比较细菌负荷，肺部炎症， Mtb感染的hCD 1 Tg/LDLR-/-小鼠中自身反应性和Mtb脂质特异性T细胞应答的大小 伴有或不伴有高脂血症。虽然已知肽特异性T细胞具有独特的效应和记忆， 表型，记忆组1 CD 1限制性T细胞的特性仍然难以捉摸。在目标2中，我们将 确定记忆MA/CD 1b特异性T细胞的功能特性和保护机制 在用含MA的纳米颗粒（MA-NP）接种的小鼠中。要识别与以下各项相关的共同特征，请执行以下操作 Mtb-脂质特异性记忆T细胞，我们将比较记忆MA/CD 1b特异性T细胞与葡萄糖 单霉菌酸盐/CD 1b特异性T细胞，分离自表达单霉菌酸盐/CD 1b特异性T细胞的新型TCR转基因小鼠模型。 保守的种系编码的分枝菌酰脂质反应性（GEM）TCR。最后，转录和功能 通过两种疫苗接种方法，MA-NP和免疫接种方法， 减毒的Mtb菌株，将比较它们对随后用Mtb攻击的反应， 评估。总的来说，这些研究将为更好地理解脂质特异性T细胞的作用铺平道路。 细胞在各种感染性疾病的相关并发症条件。

PROJECT SUMMARY Group 1 CD1-restricted T cells are members of the unconventional T cell family that recognize self- and microbial lipid antigens presented by CD1a, CD1b, and CD1c molecules. Group 1 CD1-restricted T cells have been implicated to play critical roles in various autoimmune and infectious diseases, in particular Mycobacterium tuberculosis (Mtb) infection. While group 1 CD1-restricted T cells represent a substantial part of the T cell repertoire in humans, further understanding of their in vivo function and regulation in immune response has been stymied by the lack of group 1 CD1 expression in mice. We have previously generated a transgenic mouse model possessing the entire human group 1 CD1 locus (hCD1Tg) and TCR transgenic mouse models with Mtb lipid and self-lipid specificity. We demonstrated that both mycolic acid (MA)-specific and self-lipid-specific CD1b-restricted T cells confers protection against Mtb infection. In addition, chronic activation of CD1b autoreactive T cells can lead to the development of psoriasis-like skin inflammation in an ApoE-deficient mouse model of hyperlipidemia. As hyperlipidemia is a common condition in HIV-infected individuals and the general population, we aim to further understand how it may affect the function of group 1 CD1-restricted T cells during infection using Mtb infection as a model. In Aim 1, TCR transgenic mouse models in hCD1Tg/LDLR-/- background will be used to determine the impact of diet- induced hyperlipidemia on self- and microbial lipid-specific T cells and elucidate the molecular and cellular mechanisms mediate such effect. The impact of hyperlipidemia on the polyclonal group 1 CD1-restricted T cell responses to Mtb infection will also be determined by comparing bacterial burden, lung inflammation, and magnitude of autoreactive and Mtb lipid-specific T cell responses in Mtb-infected hCD1Tg/LDLR-/- mice with or without hyperlipidemia. While peptide-specific T cells are known to have distinct effector and memory phenotypes, the properties of memory group 1 CD1-restricted T cells remain elusive. In Aim 2, we will determine functional properties and protective mechanism of memory MA/CD1b-specific T cells generated in mice vaccinated with MA containing nanoparticle (MA-NP). To identify common features associated with Mtb-lipid specific memory T cells, we will compare memory MA/CD1b-specific T cells to glucose monomycolate/CD1b-specific T cells, isolated from a novel TCR transgenic mouse model expressing a conserved germline-encoded mycolyl lipid-reactive (GEM) TCR. Lasty, the transcriptional and functional properties of memory MA/CD1b-specific T cells elicited by two vaccination approaches, MA-NP and an attenuated Mtb strain, will be compared and their response to subsequent challenge with Mtb will be evaluated. Collectively, these studies will pave way to better understanding of the role of lipid-specific T cells in various infectious disease in a relevant comorbidity condition.