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-艾滋病毒混合感染结果的因素，并 优先考虑治疗免疫抑制人群中耐药结核病的新治疗方法。最近， 已有研究表明，髓系来源的抑制细胞(MDSC)的药理调节可能是 结核病抗菌治疗的替代方案。MDSC是一种暂时的未成熟髓系细胞群体，起源于 来自一个普通的祖细胞，已经被证明通过招募T调节细胞来阻止T细胞的激活 诱导免疫细胞上PD-1的表达。在癌症和慢性传染病中， MDSC与免疫抑制和局部抑制宿主的免疫反应有关 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是否是免疫辅助治疗结核病的有效靶点 在受抑制的人群中，它们在结核病中的作用需要阐明。我们假设MDSC 在结核感染过程中，通过影响肺组织的空间浸润，促进肺内局部免疫抑制 免疫细胞与常驻巨噬细胞/单核细胞数量减少和/或抗菌效果 肉芽肿内的人群。髓系抑制细胞(MDSC)与免疫相关。 在组织微环境中局部抑制和抑制宿主的免疫反应，但其作用 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 是结核病辅助治疗的有用靶点，通过建立数量和本地化模式 利用新的成像平台组织环在人和小鼠结核分枝杆菌感染肺中的MDSC 免疫荧光(t-CyCIF)在肉芽肿的背景下评估MDSC。我们的长期目标是 研究是为了确定MDSC的功能和贩运可以在多大程度上得到调节 从药理上改善结核病的治疗结果。通过确定空间共局部化 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 不同品系近交系(DO)小鼠结核感染的组织定位与控制 MDSC在结核病治疗中作为宿主导向治疗的靶点。总而言之，我们将使用新的方法，t- CyCIF，与人类遗传多样性的小鼠模型相结合，产生关于这一角色的新知识 多药耐药干细胞在结核病中的应用。改变MDSC扩张和渗透的方法可能有助于结核病疫苗的设计和 免疫疗法可促进HIV感染者和非感染者中分枝杆菌的清除。

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.