Myeloid-Derived Suppressor Cells in Tuberculosis Granuloma Structure and Function

项目摘要 迫切需要确定导致结核病和艾滋病毒合并感染结果的因素， 优先考虑新的治疗方式，以治疗免疫抑制人群中的耐药结核病。最近， 已经提出，骨髓源性抑制细胞（MDSC）的药理学调节可能是 结核病抗菌治疗的替代方案。MDSC是一种短暂的未成熟骨髓细胞群， 从共同的祖细胞，已被证明可以通过募集T调节细胞来阻断T细胞活化。 淋巴细胞和诱导免疫细胞上的PD-1表达。在癌症和慢性传染病中， MDSC与免疫抑制和宿主局部免疫反应的减弱有关 在组织微环境中，但MDSC在结核分枝杆菌（Mtb）疾病进展中的作用是 不清楚为了确定MDSC是否是结核病免疫治疗的有效靶点， 由于结核病的发病率低，因此需要阐明它们在结核病中的作用。我们假设MDSC 有助于肺结核感染过程中的局部免疫抑制，通过影响肺结核的空间浸润， 免疫细胞和减少驻留巨噬细胞/单核细胞的数量和/或抗微生物效力 肉芽肿内的人群。髓源性抑制细胞（MDSC）与免疫相关， 抑制和阻尼宿主的免疫反应局部组织微环境，但作用 MDSC在结核分枝杆菌（Mtb）疾病进展中的作用尚不清楚。我们建议确定MDSC是否 是结核病连续治疗的有用靶点， MDSC在人类和小鼠Mtb感染的肺中使用新型成像平台，组织循环 免疫荧光（t-CyCIF）来评估肉芽肿背景下的MDSC。我们的长期目标是 研究的目的是确定MDSC的功能和交易可以被调节到什么程度 改善结核病治疗结果。通过确定空间共定位的 结核肉芽肿中MDSC与其他免疫细胞的关系及MDSC免疫相关性的建立 组织定位与结核病感染和控制的多样性远交（DO）小鼠，我们可以评估 MDSC作为TB治疗中宿主导向疗法的靶点。总之，我们将使用新的方法，t- CyCIF，再加上人类遗传多样性的小鼠模型，以产生关于作用的新知识， MDSC在结核病中的应用改变MDSC的扩增和浸润的方法可有助于TB疫苗设计和 免疫疗法，以促进结核分枝杆菌清除在艾滋病毒感染和未感染的患者。

Project Summary There is a critical need for identification of factors contributing to TB-HIV co-infection outcomes and to prioritize new treatment modalities for treating drug-resistant TB in immune suppressed populations. Recently, it has been suggested that pharmacologic modulation of myeloid-derived suppressor cells (MDSC) may be an alternative to antimicrobial therapy for TB. MDSC are a transient immature myeloid cell population derived from a common progenitor cell, that have been shown to block T cell-activation by recruiting T-regulatory lymphocytes and inducing PD-1 expression on immune cells. In both cancer and chronic infectious diseases, MDSC have been associated with immune-suppression and dampening of the host’s immune response locally in tissue microenvironments, but the role of MDSC in Mycobacterium tuberculosis (Mtb) disease progression is unclear. In order to determine if MDSC are a useful target for adjunctive therapy for TB disease in immune suppressed populations, their role in TB disease needs to be elucidated. We hypothesize that MDSC contribute to local immune suppression in the lung during TB infection by influencing spatial infiltrates of immune cells and decreasing numbers and/or antimicrobial effectiveness of resident macrophage/monocyte populations within the granuloma. Myeloid derived suppressor cells (MDSC) have been associated with immune- suppression and dampening of the host’s immune response locally in tissue microenvironments, but the role of MDSC in Mycobacterium tuberculosis (Mtb) disease progression is unclear. We propose to determine if MDSC are a useful target for adjunctive therapy for TB disease by establishing numbers and localization patterns of MDSC in both human and mouse Mtb infected lung using a novel imaging platform, tissue cyclic immunofluorescence (t-CyCIF) to evaluate MDSC in the context of the granuloma. The long-term goal of our research is to establish the extent to which MDSC function and trafficking can be modulated pharmacologically to improve TB treatment outcomes. By determining the spatial co-localization of MDSC with other immune cells in human TB granulomas and establishing immune correlates of MDSC tissue localization with tuberculosis infection and control in Diversity Outbred (DO) mice we can evaluate MDSC as targets for host-directed therapy in TB treatment. In summary, we will use novel methodology, t- CyCIF, coupled with a mouse model of human genetic diversity, to generate new knowledge regarding the role of MDSC in TB disease. Methods to alter the expansion and infiltration of MDSC may aid TB vaccine design and immunotherapy to promote mycobacterial clearance in both HIV infected an uninfected patients.