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

项目总结 据估计，世界上三分之一的人口潜伏着感染结核分枝杆菌(Mtb)，以及 艾滋病毒感染大大增加了患结核病的风险，使艾滋病毒/结核病混合感染成为一种严重的健康问题 威胁。传统的多肽抗原特异性的CD4+和CD8+T细胞反应在适应性中发挥着重要作用 对结核分枝杆菌具有免疫力，并正在成为各种疫苗接种战略的目标。然而，脂质在体内的作用 尽管有迹象表明，结核免疫中抗原特异性CD1限制性T细胞反应仍很不清楚 在小动物模型中抗结核病潜力的研究。我们发现结核分枝杆菌脂类抗原特异性T细胞因子和 在未感染的猕猴体内可以检测到细胞毒性反应，这表明这些免疫反应可能 在早期防御结核分枝杆菌方面发挥了重要作用。此外，我们观察到显著更高的结核分枝杆菌血脂- 食蟹猴与恒河猴的特异性反应比较。利用卡介苗模型 食蟹猴暴露于分枝杆菌，表现出更强的天然Mtb脂类抗原特异性 我们的目标是确定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 也表明感染SIV的猕猴外周血结核分枝杆菌脂类抗原特异性反应下降。因此， 我们认为，SIV感染诱导宿主CD1限制性免疫反应的扰动，从而 会增加合并感染结核病的风险。这项建议的具体目标集中在 了解CD1限制性免疫反应在结核病防治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。在第一个目标中，表型和功能 系统和粘膜分枝杆菌脂质特异性T细胞的特性将在#年进行纵向检查 接种卡介苗的猕猴抗分枝杆菌效应功能及其与适应性的关系 免疫反应。抗分枝杆菌效应器的功能将通过体外评价来研究 细胞因子对脂类抗原刺激的反应，对自身结核分枝杆菌感染单核细胞的细胞毒性，以及 CD1表达的抗原提呈细胞的激活。在第二个目标中，为了了解它们在 SIV诱导结核病的重新激活，这项研究将确定SIV感染对这些效应器功能的影响 在接种了卡介苗的猕猴的血液和肺中。这些研究之所以相关，是因为它们关注的是 了解结核和艾滋病毒非人类灵长类动物模型中分枝杆菌免疫的新机制。 这些结果将为预防结核病的免疫机制提供有价值的见解，以及如何 慢病毒感染损害了这些机制，并将为探索特定的基于脂质的模式开辟新的途径 对结核病的干预。

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.