Role of Lipid Antigen-Specific T Cells in the Anti-mycobacterial Immune Response of BCG/SIV Infected Macaques

项目摘要 据估计，世界上三分之一的人口潜伏感染结核分枝杆菌（Mtb）， 艾滋病毒感染大大增加了患结核病的风险，使艾滋病毒/结核病合并感染成为严重的健康问题。 威胁传统的肽抗原特异性CD 4+和CD 8 + T细胞应答在适应性免疫中起重要作用。 结核病的免疫力，并正在通过各种疫苗接种战略的目标。然而，脂质在体内的作用 结核免疫中的抗原特异性CD 1限制性T细胞应答在很大程度上仍然是未知的， 在小动物模型中的抗结核潜力。我们已经发现Mtb脂质抗原特异性T细胞细胞因子和 在未感染的猕猴中可以检测到细胞毒性反应，这表明这些免疫反应可能 在结核病的早期防御中发挥重要作用。此外，我们观察到Mtb脂质显著升高， 与恒河猴相比，食蟹猴的特异性反应。利用BCG模型， 食蟹猴中的分枝杆菌暴露，其显示更有效的先天性Mtb脂质抗原特异性 反应，我们的目标是定义CD 1限制性免疫反应在结核病免疫中的作用。我们以前的数据 也表明SIV感染的猕猴的外周血Mtb脂质抗原特异性应答下降。因此 我们提出SIV感染诱导宿主CD 1限制性免疫应答的扰动， 导致合并感染结核病的风险增加。本提案的具体目标是： 了解CD 1限制性免疫应答在结核病保护中的体内作用及其对结核病的影响 SIV感染对其抗分枝杆菌效应子功能的影响。在第一个目标中， 系统和粘膜分枝杆菌脂质特异性T细胞的特征将在 BCG接种猕猴以确定抗分枝杆菌效应子功能及其与适应性 免疫反应。抗分枝杆菌效应子功能将通过体外评价 对脂质抗原刺激的细胞因子应答，对自体Mtb感染的单核细胞的细胞毒性，和 活化表达CD 1的抗原呈递细胞。在第二个目标中，为了了解它们在 SIV诱导的TB再激活，该研究将确定SIV感染对这些效应器功能的影响 血液和肺中的细菌数量。这些研究是相关的，因为它们关注的是 了解结核病和艾滋病非人灵长类动物模型中分枝杆菌免疫的新机制。 这些结果将为了解结核病的免疫保护机制以及如何预防结核病提供有价值的见解。 慢病毒感染损害这些机制，并将开辟新的途径，探索特定的脂质为基础的模式 结核病的干预。

PROJECT SUMMARY An estimated one third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), and HIV infection significantly increases the risk of developing TB, making HIV/TB co-infection a serious health threat. Conventional peptide antigen-specific CD4+ and CD8+ T cell responses play important roles in adaptive immunity to Mtb and are being targeted by various vaccination strategies. However, the in vivo role of lipid antigen-specific CD1-restricted T cell responses in TB immunity remains largely unknown despite an indication of anti-TB potential in small animal models. We have found that Mtb lipid antigen-specific T cell cytokine and cytotoxic responses can be detected in uninfected macaques suggesting that these immune responses may play important roles in early defense against Mtb. Furthermore, we observed significantly higher Mtb lipid- specific responses in cynomolgus macaques in comparison to rhesus macaques. Utilizing the BCG model of mycobacterial exposure in cynomolgus macaques that display more potent innate Mtb lipid antigen-specific responses, we aim to define the role of CD1-restricted immune responses in TB immunity. Our previous data also indicate a decline in peripheral blood Mtb lipid antigen-specific responses of SIV-infected macaques. Thus we propose that SIV infection induces perturbations in the host CD1-restricted immune responses that contribute to increased risk of TB in co-infection. The specific aims of this proposal are focused on the understanding of the in vivo role of CD1-restricted immune responses in protection against TB and the impact of SIV infection on their anti-mycobacterial effector functions. In the first aim, the phenotypic and functional characteristics of systemic and mucosal mycobacterial lipid-specific T cells will be examined longitudinally in BCG-inoculated macaques to determine anti-mycobacterial effector functions and relationship with adaptive immune responses. The anti-mycobacterial effector functions will be investigated by evaluation of in vitro cytokine responses to lipid antigen-stimulation, cytotoxicity towards autologous Mtb-infected monocytes, and activation of CD1-expressing antigen presenting cells. In the second aim, in order to understand their role in SIV-induced reactivation of TB, the study will determine the impact of SIV infection on these effector functions in blood and lungs of BCG-vaccinated macaques. These studies are relevant because they focus on understanding novel mechanisms of mycobacterial immunity in the nonhuman primate model of TB and HIV. The results will provide valuable insights into the immune mechanisms of protection against TB, and how lentiviral infection impairs these mechanisms, and will open new avenues to explore specific lipid-based modes of intervention in TB.