The Role of SLAMF1 in TB Immunity

项目摘要 结核分枝杆菌（Mtb）是全世界因感染而死亡的主要原因。MTB能够逃避 先天免疫防御系统通过在巨噬细胞中生长。大多数人对Mtb产生强烈的CD 4 + T细胞应答 感染，这是重要的宿主防御;然而，尽管显着的T细胞反应，5-10%的感染， 个体将发展为活动性结核病（TB）。这一建议背后的基本原理是，如果我们更好地理解 在CD 4 + T细胞提供部分保护的基础上，我们可以在细胞内增强这些反应。 治疗的背景下，以促进杀菌免疫和这种反应可能作为相关的 疫苗的保护。由于先前的工作表明，CD 4 + T细胞必须直接识别抗原， 为了促进Mtb控制，我们试图鉴定介导Mtb的不溶性因子， 巨噬细胞-T细胞相互作用。我们发现，细胞表面受体信号淋巴细胞激活 分子（SLAM）家族成员（SLAM/SLAMF 1/CD 150）在Mtb感染的小鼠中诱导超过400倍。 巨噬细胞应答抗原特异性CD 4 + T细胞。此外，SLAMF 1在人乳腺癌组织中的表达更高， 感染的巨噬细胞与同一孔中未感染的巨噬细胞相比。此外，SLAMF 1是 当它们与感染的巨噬细胞一起孵育时，SLAMF 1通过同型 相互作用; SLAMF 1表达细胞刺激其他SLAMF 1表达细胞。因此，SLAMF 1准备 介导直接的巨噬细胞-T细胞相互作用并增强两种细胞的抗微生物活性。先前 研究证实，SLAMF 1在CD 4 + T细胞中作为共刺激分子发挥作用，而在巨噬细胞中， SLAMF 1激活NADPH氧化酶和溶酶体运输，这是我们以前研究的抗微生物反应。 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SLAMF 1诱导和 T细胞也与用IV BCG接种的非人灵长类动物的保护相关， 前所未有的保护。在这里，我们将测试我们的假设，SLAMF 1信号之间的感染 巨噬细胞和CD 4 + T细胞促进对Mtb的控制，并且进一步增强SLAMF 1信号传导增强了 主机保护。我们将检查Slamf 1的表达和定位，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感染调节 和抗原特异性T细胞。我们将确定其在非人灵长类动物肉芽肿中的表达谱。我们将 确定SLAMF 1是否限制人和鼠巨噬细胞中Mtb的细胞内生长，以及是否 SLAMF 1激活增强细胞内Mtb控制。最后，我们将评估SLAMF 1在 vivo.因此，在本项目结束时，我们将确定SLAMF 1介导巨噬细胞- T细胞 细胞信号传导以促进Mtb的细胞内控制。我们的发现将使未来的研究成为可能 用于靶向该途径进行治疗干预，并将其作为保护的相关因素进行评估。鉴于 结核病给全球造成了巨大负担，我们的项目有可能对人类健康产生巨大影响。

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.