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

项目说明结核病(TB)仍然是全球死亡/发病的主要原因之一，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，结核病已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，全球结核病控制似乎很困难。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。我们最近进行的一系列新的观察表明，Vγ2Vδ2T细胞是人类/灵长类动物中占主导地位的γδT细胞亚群，在宿主反应和免疫调节中发挥作用，并有助于抗结核分枝杆菌(Mtb)等感染的抗微生物免疫。特别是阐明了Mtb磷酸抗原(E)-4-羟基-3-甲基-2-烯基焦磷酸(HMBPP)能与Vγ2Vδ2T细胞表面分子结合，与Vγ2Vδ2T细胞上的TcR结合，并能激活/扩增V DNA 2V Tcr。重要的是，HMBPP联合IL-2处理猕猴可诱导多功能V-γ-2V-δ-2T效应细胞大量扩增。HMBPP扩增的V-γ-2V-δ-2T效应细胞可在呼吸道/肺内聚集，产生抗结核细胞因子干扰素γ/穿孔素/颗粒溶素，在结核分枝杆菌感染后产生抗结核免疫，甚至诱导机体对暴发性肺鼠疫的肺内环境保护。基于这些发现，我们推测V-γ-2V-δ-2T细胞在结核分枝杆菌感染中可能发挥抗结核效应、体内平衡介质和免疫调节剂的作用，增强T细胞应答，并产生抗结核免疫。为了检验这一假设，我们将.确定HMBPP-扩展的机制 Vγ2Vδ2T效应细胞具有抗结核免疫功能。确定在慢性结核分枝杆菌感染期间Vγ2Vδ2 T细胞靶向治疗是否可以为严重的结核病病变和/或结核空洞提供免疫疗法。确定Vγ2Vδ2 T细胞的hMBPP/IL-2扩增是否能克服CD 4/CD 8 T细胞的抑制反应，并在低CD 4细胞数的SIV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 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.