Ag-specific gamma delta T cells and immunity to TB/AIDS-related TB

Ag 特异性 γ δ T 细胞和对结核病/艾滋病相关结核病的免疫力

• 批准号: 8846156
• 负责人: Zheng W Chen
• 金额: $ 55.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-03 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846156
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Antibiotics; Antitubercular Agents; Binding; Biological Response Modifiers; CD4 Lymphocyte Count; CD8B1 gene; Chronic; Communicable Diseases; Data; Depressed mood; Diphosphates; Drug resistance; Drug resistance in tuberculosis; Effector Cell; Extreme drug resistant tuberculosis; HIV; Health; Human; Immune; Immune response; Immunity; Immunotherapeutic agent; Infection; Interferon Type II; Interleukin-2; Intervention; Lesion; Lung; Macaca; Mediator of activation protein; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Pharmaceutical Preparations; Play; Pneumonic Plague; Primates; Regimen; Regulation; Role; Surface; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tuberculosis; Vaccines; antimicrobial; base; cytokine; granulysin; hydroxy compound; immune function; in vivo; mortality; nonhuman primate; novel; perforin; response; simian human immunodeficiency virus; small molecule; trafficking; tuberculosis immunity

DESCRIPTION (provided by applicant): Project Description Tuberculosis (TB) remains one of the major causes of global mortality/morbidity, and has become increasingly prevalent and deadly as a result of HIV/AIDS and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Global control of TB appears difficult because of the lack of an effective protective vaccine and lack of sterilizing drugs. Since drug resistance is likely to increase, there is a pressed need to develop effective vaccine or immunotherapeutic. We have recently made serial novel observations suggesting that Vγ2Vδ2 T cells, the dominant γδ T-cell subset in humans/primates, play a role in host response and immune regulation, and contribute to anti-microbial immunity against infections including M. tuberculosis (Mtb). Particularly, we elucidate that Mtb phosphoantigen (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) can associate with APC surface molecule, bind to TCR on Vγ2Vδ2 T cells, and activate/expand Vγ2Vδ2 T cells. Importantly, HMBPP plus IL-2 treatment of macaques induces massive expansion of multi-functional Vγ2Vδ2 T effector cells. HMBPP-expanded Vγ2Vδ2 T effector cells can traffic to and accumulate in airway/lung, produce anti-TB cytokines IFNγ/perforin/granulysin, confer anti-TB immunity after Mtb infection and even induce homeostatic protection against fulminating pneumonic plague lesions in lungs. Based on these findings, we hypothesize that Vγ2Vδ2 T cells can function as anti-TB effectors, homeostatic mediators and immune regulators enhancing CD4/CD8 T-cell responses, and confer anti-TB immunity in Mtb infection. To test this hypothesis, we will I. Determine mechanisms by which HMBPP-expanded Vγ2Vδ2 T effector cells confer anti- TB immunity. II. Determine whether Vγ2Vδ2 T-cell-targeted treatments during chronic Mtb infection can confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Determine if HMBPP/IL-2 expansion of Vγ2Vδ2 T cells can overcome depressed responses of CD4/CD8 T cells and protect against HIV-related TB in SHIV-infected macaques with low CD4 counts.

结核病（TB）仍然是全球死亡/发病的主要原因之一，并且由于艾滋病毒/艾滋病以及耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）的出现而变得越来越普遍和致命。由于缺乏有效的保护性疫苗和消毒药物，全球控制结核病似乎很困难。由于耐药性可能增加，迫切需要开发有效的疫苗或免疫制剂。我们最近进行了一系列新的观察，表明Vγ 2 V δ2 T细胞，在人类/灵长类动物中占优势的γδ T细胞亚群，在宿主反应和免疫调节中发挥作用，并有助于抗微生物免疫对抗包括M.结核病（Mtb）。特别地，我们阐明了Mtb磷酸化抗原（E）-4-羟基-3-甲基-丁-2-烯基焦磷酸（HMBPP）可以与APC表面分子结合，结合Vγ 2 V δ2 T细胞上的TCR，并激活/扩增Vγ 2 V δ2 T细胞。重要的是，猕猴的HMBPP加IL-2处理诱导多功能Vγ 2 VS 2 T效应细胞的大量扩增。HMBPP扩增的Vγ 2 V δ2 T效应细胞可以运输到气道/肺并在气道/肺中积累，产生抗TB细胞因子IFNγ/穿孔素/颗粒溶素，在Mtb感染后赋予抗TB免疫力，甚至诱导针对肺中暴发性肺鼠疫病变的稳态保护。基于这些发现，我们假设Vγ 2 VS 2 T细胞可以作为抗TB效应器、稳态介导剂和免疫调节剂增强CD 4/CD 8 T细胞应答，并在Mtb感染中赋予抗TB免疫力。为了验证这个假设，我们将。确定HMBPP扩增的机制 Vγ 2 VS 2 T效应细胞赋予抗TB免疫。二.确定慢性Mtb感染期间Vγ 2 V δ2 T细胞靶向治疗是否可以赋予针对严重TB病变和/或TB空洞的免疫治疗。三.确定Vγ 2 V δ2 T细胞的HMBPP/IL-2扩增是否可以克服CD 4/CD 8 T细胞的抑制反应，并在具有低CD 4计数的SHIV感染的猕猴中预防HIV相关TB。