Group 1 CD1 in Infectious Disease and T Cell Development

描述（由申请人提供）：已证明人1型CD 1分子CD 1a、CD 1b和CD 1c可将内源性和分枝杆菌衍生的脂质抗原呈递给各种T细胞亚群。第1组CD 1限制性免疫应答与抗分枝杆菌免疫有关;然而，由于缺乏合适的动物模型，它们在感染中的作用尚不清楚。我们已经产生了转基因小鼠（hCD 1 Tg），表达人类1组CD 1分子的模式类似于人类，并支持T细胞的发展，仅限于1组CD 1。结核分枝杆菌（Mtb）感染和Mtb脂质免疫均在hCDlTg小鼠中引发组1 CD 1限制性Mtb-脂质抗原特异性T细胞应答，并且二次免疫诱导比一次免疫更快速的应答。此外，从hCD 1 Tg小鼠产生的第1组CD 1限制性T细胞可以识别人类中描述的分枝杆菌抗原。总之，这些数据表明，第1组CD 1限制性T细胞在适应性免疫中发挥作用，并可作为结核分枝杆菌疫苗开发的靶点。该提案旨在研究Mtb感染期间第1组CD 1限制性T细胞的体内功能，并使用hCD 1 Tg小鼠模型测试靶向第1组CD 1限制性T细胞的Mtb脂质疫苗的功效。在目的1中，我们建议确定由第1组CD 1在结核分枝杆菌感染的hCD 1 Tg小鼠中呈现的免疫显性结核分枝杆菌抗原，并评估这些抗原在脂质疫苗中对结核分枝杆菌攻击的保护效力。在目的2中，我们提出产生表达特异性针对不同Mtb脂质抗原的TCR的逆转录小鼠，并使用过继转移方法研究这些T细胞的活化动力学、效应子功能和保护作用。虽然第1组CD 1限制性Mtb脂质抗原特异性T细胞直接识别外来抗原，但第1组CD 1限制性自身反应性T细胞可在感染期间通过识别TLR成熟抗原呈递细胞呈递的内源性抗原而被激活，并有助于先天性抗分枝杆菌应答，类似于第2组CD 1d限制性NKT细胞所述的情况。因此，在我们的第三个目标中，我们将使用TCR转基因模型研究结核分枝杆菌感染期间自身反应性第1组CD 1限制性T细胞的发育要求和功能。总的来说，这些研究将使我们更好地了解第1组CD 1限制性T细胞如何有助于对Mtb的保护性免疫，以及它们是否可以成为开发基于脂质抗原的Mtb疫苗的靶点。

DESCRIPTION (provided by applicant): The human group 1 CD1 molecules CD1a, CD1b, and CD1c have been shown to present both endogenous and mycobacterial-derived lipid antigens to various subsets of T cells. Group 1 CD1- restricted immune responses have been implicated in anti-mycobacterial immunity; however, their role in infection is unknown due to the lack of a suitable animal model. We have generated transgenic mice (hCD1Tg) that express human group 1 CD1 molecules in a pattern similar to humans, and support the development of T cells that are restricted to group 1 CD1. Both infection with Mycobacterium tuberculosis (Mtb) and immunization with Mtb lipids elicit group 1 CD1-restricted Mtb- lipid antigen-specific T cell responses in hCD1Tg mice, and secondary immunization induces more rapid responses than primary immunization. In addition, group 1 CD1-restricted T cells generated from hCD1Tg mice can recognize mycobacterial antigens described in humans. Taken together, these data indicate that group 1 CD1-restricted T cells play a role in adaptive immunity and could serve as targets for Mtb vaccine development. This proposal seeks to study the in vivo function of group 1 CD1-restricted T cells during Mtb infection and to test the efficacy of a lipid-based vaccine for Mtb that targets group 1 CD1-restricted T cells using the hCD1Tg mouse model. In Aim 1, we propose to identify immunodominant Mtb antigens presented by group 1 CD1 in Mtb-infected hCD1Tg mice and evaluate the protective efficacy of these antigens in a lipid vaccine upon Mtb challenge. In Aim 2, we propose to generate retrogenic mice which express TCRs specific to distinct Mtb lipid antigens, and investigate the activation kinetics, effector function, and protective role of these T cells using an adoptive transfer approach. While group 1 CD1-restricted Mtb lipid antigen-specific T cells recognize foreign antigens directly, group 1 CD1-restricted autoreactive T cells may be activated during infection through recognition of endogenous antigen presented by TLR-matured antigen presenting cells and contribute to innate anti-mycobacterial responses, analogous to what has been described for group 2 CD1d-restricted NKT cells. In our third Aim, we will therefore investigate the developmental requirements and function of autoreactive group 1 CD1-restricted T cells during Mtb infection using a TCR transgenic model. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted T cells contribute to protective immunity against Mtb and whether they can be targeted for the development of lipid antigen-based Mtb vaccines.