The Role of SLAMF1 in TB Immunity

项目总结 结核分枝杆菌(Mtb)是世界范围内主要的感染致死原因。MTB能够躲避 巨噬细胞中生长的先天免疫防御系统。大多数人对结核分枝杆菌产生强大的CD4+T细胞反应 感染，这对宿主防御很重要；然而，尽管有明显的T细胞反应，5%-10%的感染 个人会患上活动性结核病(TB)。这一提议背后的理由是，如果我们更好地理解 在CD4+T细胞提供的部分保护的基础上，我们可以在 促进绝育免疫的治疗方法的背景和这种反应可能与 对疫苗的保护。因为以前的研究表明，CD4+T细胞必须直接识别抗原 为了促进结核分枝杆菌的控制，我们试图确定介导结核分枝杆菌控制的非可溶性因子。 巨噬细胞与T细胞的相互作用。我们发现，细胞表面受体信号转导淋巴细胞激活 分子(SLAM)家族成员(SLAM/SLAMF1/CD150)在结核分枝杆菌感染中诱导400多倍 巨噬细胞对抗原特异性的CD4+T细胞的反应。此外，SLAMF1的表达水平更高 同一井中感染的巨噬细胞与未感染的巨噬细胞的比较。此外，SLAMF1是 当T细胞与感染的巨噬细胞孵育时，T细胞被诱导。通过同型的SLAMF1信号 相互作用：表达SLAMF1的细胞刺激其他表达SLAMF1的细胞。因此，SLAMF1准备好 介导巨噬细胞与T细胞的直接相互作用，增强两种细胞的抗菌活性。上一首 研究证实，SLAMF1在CD4+T细胞中发挥共刺激分子的作用，而在巨噬细胞中则是如此 SLAMF1激活NADPH氧化酶和溶酶体运输，这是我们之前 显示在结核分枝杆菌感染期间受损。值得注意的是，我们发现SLAMF1-在巨噬细胞和 在接种IVBCG的非人灵长类动物中，T细胞也与保护相关，这提供了一种 前所未有的保护水平。在这里，我们将检验我们的假设，即SLAMF1信号在感染 巨噬细胞和CD4+T细胞促进Mtb的控制，进一步增强SLAMF1信号转导 主机保护。我们将检查Slamf1的表达和定位，以确定它是否存在于 位于免疫突触的细胞表面，与结核分枝杆菌吞噬小体相关，并受结核分枝杆菌感染的调节 和抗原特异性T细胞。我们将确定它在非人灵长类肉芽肿中的表达情况。我们会 确定SLAMF1是否限制人和小鼠巨噬细胞中结核分枝杆菌的细胞内生长，以及是否 SLAMF1的激活增强了细胞内Mtb的控制。最后，我们将评估SLAMF1在 活着。因此，在本项目结束时，我们将确定SLAMF1介导巨噬细胞-T 细胞发出信号促进结核分枝杆菌的细胞内控制。我们的发现将使未来的研究成为可能 将这一途径作为治疗干预的靶点，并将其作为保护的相关性进行评估。给定 作为全球结核病的巨大负担，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.