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

脂质抗原特异性 T 细胞在 BCG/SIV 感染的猕猴抗分枝杆菌免疫反应中的作用

• 批准号: 9767660
• 负责人: Namita Rout
• 金额: $ 21.25万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-21 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767660
• 关键词: Address; Adult; Aerosols; Animal Model; Antigen-Presenting Cells; Antigens; Antitubercular Agents; Autologous; BCG Live; BCG Vaccine; Biopsy; Blood; Bronchoalveolar Lavage; CD8-Positive T-Lymphocytes; Cavia; Cell physiology; Cells; Cessation of life; Characteristics; Clinical; Data; Development; Evaluation; Exhibits; Exposure to; Gene Expression Profile; Genes; Goals; HIV; HIV Infections; HIV/TB; Health; Human; Immune; Immune response; Immunity; Impairment; In Vitro; Individual; Infection; Interferon Type II; Intervention; Knowledge; Lipids; Lung; Macaca; Macaca mulatta; Mediating; Modeling; Mucous Membrane; Mus; Mycobacterium Infections; Mycobacterium bovis; Mycobacterium tuberculosis; Peptides; Phenotype; Pilot Projects; Play; Population; Predisposition; Protein Isoforms; Pulmonary Pathology; Pulmonary Tuberculosis; Recombinant Proteins; Recombinants; Regimen; Resistance; Risk; Role; SIV; System; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; adaptive immune response; adaptive immunity; antigen-specific T cells; arm; base; co-infection; cytokine; cytotoxic; cytotoxicity; design; immune function; improved; in vivo; insight; monocyte; mycobacterial; nonhuman primate; novel; peripheral blood; prevent; prospective; protective effect; rectal; response; tool; tuberculosis immunity; vaccination strategy

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.

项目摘要 估计全球三分之一的人口受到结核分枝杆菌（MTB）和 艾滋病毒感染显着增加了患结核病的风险 威胁。常规的肽抗原特异性CD4+和CD8+ T细胞反应在自适应中起重要作用 对MTB的免疫力，并由各种疫苗接种策略作为目标。但是，脂质的体内作用 尽管有指示 小动物模型中的抗TB潜力。我们发现MTB脂质抗原特异性T细胞因子和 可以在未感染的猕猴中检测到细胞毒性反应，这表明这些免疫反应可能 在对MTB的早期防御中发挥重要作用。此外，我们观察到MTB脂质明显更高 与恒河猕猴相比，膀胱猕猴中的特定反应。利用BCG模型 甲状腺猕猴中的分枝杆菌暴露，显示出更有效的先天MTB脂质抗原特异性 反应，我们旨在定义CD1限制免疫反应在结核病免疫中的作用。我们以前的数据 还表明外周血MTB脂质抗原特异性反应的下降。因此 我们建议SIV感染会引起宿主CD1限制的免疫反应的扰动 有助于增加联合感染的结核病风险。该提案的具体目的是 了解CD1限制免疫反应在保护TB中的体内作用和影响 SIV感染在其抗细菌效应子功能上。在第一个目标中，表型和功能 全身性和粘膜分枝杆菌脂质特异性T细胞的特征将在纵向上检查 BCG接种猕猴以确定抗细菌效应子功能以及与自适应的关系 免疫反应。抗细菌效应子功能将通过评估体外研究 细胞因子对脂质抗原刺激的反应，对自体MTB感染的单核细胞的细胞毒性和 表达CD1的抗原呈递细胞的激活。在第二个目标中，为了了解他们在 SIV诱导的TB重新激活，该研究将确定SIV感染对这些效应子功能的影响 在BCG接种猕猴的血液和肺中。这些研究很重要，因为它们专注于 了解TB和HIV的非人类灵长类动物模型中分枝杆菌免疫的新型机制。 结果将为防止结核病的免疫机制以及如何提供宝贵的见解，以及如何 慢病毒感染会损害这些机制，并将开放新的途径以探索特定的基于脂质的模式 干预结核病。