The Role of SLAMF1 in TB Immunity

SLAMF1 在结核病免疫中的作用

基本信息

批准号：
10172847
负责人：
JENNIFER A PHILIPS
金额：
$ 19.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172847
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 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

项目摘要

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.

项目摘要结核分枝杆菌（MTB）是世界范围内死亡的主要原因。 MTB能够逃避通过在巨噬细胞中生长的先天免疫防御能力。大多数人会发展出强大的CD4+ T细胞对MTB的反应感染，这对于宿主防御很重要；然而，尽管T细胞反应明显，但感染了5-10％个体将发展活跃的结核病（TB）。该提议背后的理由是，如果我们更好地理解 CD4+ T细胞提供的部分保护的基础，我们可以增强这些反应治疗剂的背景促进免疫和此类反应可能是相关的保护疫苗。由于以前的工作表明CD4+ T细胞必须直接识别抗原呈现细胞以促进MTB控制，我们试图确定介导的非溶因因素巨噬细胞-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（大满贯）家族成员（SLAM/SLAMF1/CD150）在MTB感染中被诱导超过400倍巨噬细胞响应抗原特异性CD4+ T细胞。此外，SlAMF1的表达更高与同一孔中未感染的巨噬细胞相比，感染的巨噬细胞。此外，Slamf1是当T细胞与感染的巨噬细胞孵育时，在T细胞上诱导。 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个细胞的抗菌活性。以前的研究表明，slAMF1在CD4+ T细胞中充当共刺激分子，而在巨噬细胞中 SLAMF1激活NADPH氧化酶和溶酶体运输，抗菌反应，我们先前显示在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细胞还与以IV BCG接种的非人类灵长类动物的保护相关，这提供了空前的保护水平。在这里，我们将测试我们的假设，即感染的SLAMF1信号传导巨噬细胞和CD4+ T细胞促进了MTB的控制，并进一步增强了SLAMF1信号传导主机保护。我们将检查SLAMF1表达和本地化，以确定它是否存在于在免疫突触处的细胞表面与MTB吞噬体相关，并受MTB感染调节和抗原特异性T细胞。我们将确定其在非人类灵长类动物颗粒中的表达曲线。我们将确定SLAMF1是否限制了人类和鼠巨噬细胞中MTB的细胞内生长以及是否限制 SLAMF1激活增强了细胞内MTB对照。最后，我们将评估slamf1的重要性体内。因此，在该项目的结论结束时，我们将确定SLAMF1介导了巨噬细胞-T 细胞信号传导以促进MTB的细胞内控制。我们的发现将使以后的研究能够研究潜力用于针对治疗干预的这一途径，并将其评估为保护的相关性。鉴于 TB的全球负担很大，我们的项目有可能对人类健康产生巨大影响。