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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：
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
项目类别：
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

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.

项目总结