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

项目概要 据估计，世界上三分之一的人口潜伏感染结核分枝杆菌 (Mtb)，并且 HIV 感染显着增加患结核病的风险，使 HIV/TB 合并感染成为严重的健康问题 威胁。传统的肽抗原特异性 CD4 和 CD8 T 细胞反应在适应性中发挥重要作用 对 Mtb 具有免疫力，并成为各种疫苗接种策略的目标。然而，脂质在体内的作用 尽管有迹象表明，结核病免疫中抗原特异性 CD1 限制性 T 细胞反应仍然很大程度上未知 小动物模型中的抗结核潜力。我们发现 Mtb 脂质抗原特异性 T 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 Mtb 的早期防御中发挥重要作用。此外，我们观察到 Mtb 脂质显着升高 与恒河猴相比，食蟹猴的特定反应。利用 BCG 模型 食蟹猴中的分枝杆菌暴露表现出更有效的先天结核分枝杆菌脂质抗原特异性 反应，我们的目的是确定 CD1 限制性免疫反应在结核病免疫中的作用。我们之前的数据 还表明感染 SIV 的猕猴外周血 Mtb 脂质抗原特异性反应下降。因此 我们认为 SIV 感染会引起宿主 CD1 限制性免疫反应的扰动，从而导致 导致合并感染结核病的风险增加。该提案的具体目标集中于 了解 CD1 限制性免疫反应在预防结核病中的体内作用及其影响 SIV 感染对其抗分枝杆菌效应功能的影响。第一个目标是表型和功能 将纵向检查全身和粘膜分枝杆菌脂质特异性 T 细胞的特征 接种卡介苗的猕猴以确定抗分枝杆菌效应功能及其与适应性的关系 免疫反应。将通过体外评估来研究抗分枝杆菌效应功能 对脂质抗原刺激的细胞因子反应、对自体 Mtb 感染的单核细胞的细胞毒性，以及 激活表达 CD1 的抗原呈递细胞。在第二个目标中，为了了解他们的作用 SIV 诱导的 TB 重新激活，该研究将确定 SIV 感染对这些效应器功能的影响 存在于接种卡介苗的猕猴的血液和肺部中。这些研究具有相关性，因为它们关注的是 了解非人类灵长类动物结核病和艾滋病毒模型中分枝杆菌免疫的新机制。 研究结果将为预防结核病的免疫机制以及如何预防结核病提供有价值的见解。 慢病毒感染会损害这些机制，并将开辟新的途径来探索特定的基于脂质的模式 结核病干预。

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.