Group 1 CD1 in Infectious Disease and T Cell Development

描述（由申请人提供）：人类1组CD1分子CD1a， CD1b和CD1c已被证明可以向各种T细胞亚群提供内源性和分枝杆菌衍生的脂质抗原。1组CD1限制性免疫反应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（hCD1Tg），以类似于人类的模式表达人类1组CD1分子，并支持局限于1组CD1的T细胞的发育。在hCD1Tg小鼠中，感染结核分枝杆菌（Mtb）和接种结核分枝杆菌脂质免疫均可引起1组cd1限制性结核分枝杆菌脂质抗原特异性T细胞反应，并且二次免疫诱导的反应比一次免疫更快。此外，hCD1Tg小鼠产生的1组cd1限制性T细胞可以识别人类描述的分枝杆菌抗原。综上所述，这些数据表明，1组cd1限制性T细胞在适应性免疫中发挥作用，可以作为结核分枝杆菌疫苗开发的靶点。本研究旨在研究Mtb感染期间1组cd1限制性T细胞的体内功能，并使用hCD1Tg小鼠模型测试针对1组cd1限制性T细胞的Mtb脂质疫苗的有效性。在Aim 1中，我们提出在Mtb感染的hCD1Tg小鼠中鉴定由1组CD1呈递的免疫优势Mtb抗原，并评估这些抗原在脂质疫苗中对Mtb攻击的保护作用。在第2项研究中，我们提出生成表达针对不同结核杆菌脂质抗原的TCRs的逆转录小鼠，并使用过继转移方法研究这些T细胞的激活动力学、效应功能和保护作用。虽然1组cd1限制性Mtb脂质抗原特异性T细胞直接识别外源抗原，但1组cd1限制性自身反应性T细胞可能在感染期间通过识别由tlr成熟抗原呈递细胞呈递的内源性抗原而被激活，并有助于先天抗分枝杆菌反应，类似于2组cd1限制性NKT细胞。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Mtb感染期间自身反应性1组cd1限制性T细胞的发育需求和功能。总的来说，这些研究将有助于更好地了解1组cd1限制性T细胞如何促进对结核分枝杆菌的保护性免疫，以及它们是否可以作为开发基于脂质抗原的结核分枝杆菌疫苗的靶点。

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. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) remains the leading cause of death due to bacterial infection. In spite of this, an effective vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of TB, is lacking. Studies in humans have shown that various lipid components of the mycobacterial cell wall can be recognized by group 1 CD1-restricted T cells, however, the contribution of these T cells to immunity against Mtb is poorly understood. This study proposes to utilize novel animal models both to characterize the immune responses mediated by group 1 CD1-restricted T cells during Mtb infection, and to test the ability of lipid vaccines to confer resistance to Mtb infection.