The Role of SLAMF1 in TB Immunity

SLAMF1 在结核病免疫中的作用

• 批准号: 10090286
• 负责人: JENNIFER A PHILIPS
• 金额: $ 23.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090286
• 关键词: Agonist; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Blood; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cause of Death; Cell Communication; Cell Surface Receptors; Cell surface; Cells; Cytoprotection; Data; Disease; Expression Profiling; Family; Family member; Future; Goals; Granuloma; Growth; Health; Hematopoietic; Host Defense; Human; Immune; Immunity; Impairment; Incubated; Individual; Infection; Infection Control; Infection prevention; Infectious Agent; Interferon Type II; Knock-out; Knockout Mice; Lead; Ligands; Ligation; Lung; Lymphocyte; Mediating; Membrane Proteins; Monkeys; Mus; Mycobacterium tuberculosis; NADPH Oxidase; Pathway interactions; Phagosomes; Population; Receptor Signaling; Role; SLAM protein; Signal Transduction; T cell response; T memory cell; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccines; Work; antigen-specific T cells; antimicrobial; cytokine; immunological synapse; in vivo; macrophage; member; nonhuman primate; novel therapeutics; novel vaccines; receptor; response; single cell analysis; single-cell RNA sequencing; therapeutic target; trafficking; tuberculosis immunity; vaccine trial

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) is the leading cause of death worldwide from an infection. Mtb is able to evade innate immune defenses by growing in macrophages. Most people develop robust CD4+ T cell responses to Mtb infection, which is important for host defense; however, despite marked T cell responses, 5-10% of infected individuals will develop active tuberculosis (TB). The rationale behind this proposal is that if we better understood the basis of the partial protection conferred by CD4+ T cells, we could enhance those responses within the context of therapeutics to promote sterilizing immunity and such responses might serve as correlates of protection for vaccines. Since previous work showed that CD4+ T cells have to directly recognize antigen presenting cells in order to promote Mtb control, we sought to identify non-soluble factors that mediate macrophage-T cell interactions. We discovered that the cell surface receptor Signaling Lymphocyte Activating Molecule (SLAM) family member (SLAM/SLAMF1/CD150) is induced more than 400-fold in Mtb-infected macrophages in response to antigen specific CD4+ T cells. In addition, SLAMF1 was more highly expressed by infected macrophages as compared to uninfected macrophages in the same well. In addition, SLAMF1 was induced on T cells when they were incubated with infected macrophages. SLAMF1 signals through homotypic interactions; SLAMF1-expressing cells stimulate other SLAMF1-expressing cells. Thus, SLAMF1 is poised to mediate direct macrophage-T cell interactions and potentiate the antimicrobial activity of both cells. Previous studies established that SLAMF1 functions as a costimulatory molecule in CD4+ T cells, while in macrophages SLAMF1 activates the NADPH oxidase and lysosomal trafficking, antimicrobial responses that we previously showed are impaired during Mtb infection. Remarkably, we found that SLAMF1-induction in macrophages and T cells also correlates with protection in nonhuman primates vaccinated with IV BCG, which affords an unprecedented level of protection. Here, we will test our hypothesis that SLAMF1 signaling between infected macrophages and CD4+ T cells promotes control of Mtb, and that further enhancing SLAMF1 signaling boosts host protection. We will examine Slamf1 expression and localization to determine whether it is present on the cell surface, at the immunological synapse, in association with Mtb phagosomes, and regulated by Mtb infection and antigen specific T cells. We will determine its expression profile in nonhuman primate granulomas. We will establish whether SLAMF1 restricts intracellular growth of Mtb in human and murine macrophages and whether SLAMF1 activation enhances intracellular Mtb control. Finally, we will evaluate the importance of SLAMF1 in vivo. Thus, at the conclusion of this project, we will have established that SLAMF1 mediates macrophage- T cells signaling to promote intracellular control of Mtb. Our discoveries will enable future studies into the potential for targeting this pathway for therapeutic intervention and evaluating it as a correlate of protection. Given the immense global burden of TB, our project has the potential to make an enormous impact on human health.

项目概要 结核分枝杆菌 (Mtb) 是全世界感染死亡的主要原因。 Mtb可以躲避 通过在巨噬细胞中生长来实现先天免疫防御。大多数人对 Mtb 产生强烈的 CD4+ T 细胞反应 感染，这对于宿主防御很重要；然而，尽管 T 细胞反应明显，5-10% 的感染者 个人会患上活动性结核病 (TB)。该提议背后的基本原理是，如果我们更好地理解 基于 CD4+ T 细胞赋予的部分保护的基础，我们可以增强 促进灭菌免疫的治疗背景和此类反应可能与 疫苗的保护。由于之前的工作表明CD4+ T细胞必须直接识别抗原 为了促进结核分枝杆菌控制，我们试图鉴定介导细胞的非可溶性因子 巨噬细胞-T 细胞相互作用。我们发现细胞表面受体信号传导淋巴细胞激活 分子 (SLAM) 家族成员 (SLAM/SLAMF1/CD150) 在 Mtb 感染者中被诱导超过 400 倍 巨噬细胞对抗原特异性 CD4+ T 细胞作出反应。此外，SLAMF1 的表达更高 受感染的巨噬细胞与同一孔中未受感染的巨噬细胞进行比较。此外，SLAMF1 是 当 T 细胞与受感染的巨噬细胞一起孵育时，它们会被诱导。 SLAMF1通过同型信号 互动；表达 SLAMF1 的细胞刺激其他表达 SLAMF1 的细胞。因此，SLAMF1 准备 介导直接巨噬细胞-T 细胞相互作用并增强两种细胞的抗菌活性。以前的 研究证实 SLAMF1 在 CD4+ T 细胞中充当共刺激分子，而在巨噬细胞中则充当共刺激分子 SLAMF1 激活 NADPH 氧化酶和溶酶体运输，以及我们之前的抗菌反应 表现出在 Mtb 感染期间受损。值得注意的是，我们发现巨噬细胞中的 SLAMF1 诱导 T 细胞还与接种 IV BCG 疫苗的非人类灵长类动物的保护相关，这提供了 前所未有的保护水平。在这里，我们将测试我们的假设，即感染者之间的 SLAMF1 信号传导 巨噬细胞和 CD4+ T 细胞促进 Mtb 的控制，并进一步增强 SLAMF1 信号传导 主机保护。我们将检查 Slamf1 表达和定位以确定它是否存在于 细胞表面，在免疫突触处，与 Mtb 吞噬体相关，并受 Mtb 感染的调节 和抗原特异性T细胞。我们将确定其在非人灵长类肉芽肿中的表达谱。我们将 确定 SLAMF1 是否限制人类和小鼠巨噬细胞中 Mtb 的细胞内生长，以及是否 SLAMF1 激活增强细胞内 Mtb 控制。最后，我们将评估 SLAMF1 在 体内。因此，在该项目结束时，我们将确定 SLAMF1 介导巨噬细胞-T 细胞信号传导促进 Mtb 的细胞内控制。我们的发现将使未来的研究成为可能 针对这一途径进行治疗干预并将其评估为保护的相关性。鉴于 结核病给全球带来了巨大的负担，我们的项目有可能对人类健康产生巨大影响。