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

项目描述（由申请人提供）：结核病（TB）仍然是全球死亡率/发病率的主要原因之一，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，结核病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，结核病的全球控制似乎很困难。由于耐药性可能会增加，因此迫切需要开发有效的疫苗或免疫疗法。我们最近做了一系列新颖的观察，表明V？2个T细胞，占主导地位？人类/灵长类动物中的t细胞亚群在宿主反应和免疫调节中发挥作用，并有助于抗感染的抗微生物免疫，包括结核分枝杆菌（Mtb）。特别是，我们阐明了Mtb磷酸化抗原(E)-4-羟基-3-甲基-2-烯基焦磷酸（HMBPP）可以与APC表面分子结合，与V？2V - 2 T细胞，激活/扩增V？2V¿2 T细胞。重要的是，HMBPP加IL-2处理猕猴可诱导多功能V？2V / 2t效应细胞。HMBPP-expanded V ?T效应细胞可在气道/肺内转运和积聚，产生抗结核细胞因子IFN？/穿孔素/颗粒素，在结核分枝杆菌感染后赋予抗结核免疫，甚至诱导对肺部暴发性肺鼠疫病变的稳态保护。基于这些发现，我们假设V？2V - 2 T细胞可作为抗结核效应剂、稳态介质和免疫调节剂，增强CD4/CD8 T细胞反应，并在结核分枝杆菌感染中赋予抗结核免疫。为了验证这一假设，我们将1 .确定hmbpp扩展V?2V？T效应细胞赋予抗结核免疫。2。确定是否V？在慢性结核感染期间，t细胞靶向治疗可赋予针对严重结核病变和/或结核空洞的免疫治疗。3。确定HMBPP/IL-2是否扩增V？2V¿2 T细胞可以克服CD4/CD8 T细胞的抑制反应，并在CD4计数低的shiv感染猕猴中预防hiv相关结核病。

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 V?2V¿2 T cells, the dominant ?¿ 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 V?2V¿2 T cells, and activate/expand V?2V¿2 T cells. Importantly, HMBPP plus IL-2 treatment of macaques induces massive expansion of multi-functional V?2V¿2 T effector cells. HMBPP-expanded V?2V¿2 T effector cells can traffic to and accumulate in airway/lung, produce anti-TB cytokines IFN?/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 V?2V¿2 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 V?2V?2 T effector cells confer anti- TB immunity. II. Determine whether V?2V¿2 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 V?2V¿2 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.