Contribution of the CD153/CD30 axis to Mycobacterium tuberculosis control in humans

项目摘要 在90%的病例中，感染结核分枝杆菌（Mtb）的健康人保持无症状。 这意味着宿主产生并维持一种部分保护性免疫应答， 包含细菌复制。当这种平衡被改变时，例如在HIV相关的CD 4 T细胞 结核病可能会发生。然而，Mtb特异性CD 4 + T细胞的确切性质，赋予免疫 保护仍然难以实现，阻碍了新疫苗的开发。现在已经明确，虽然 但是，IFNγ不足以为Mtb提供肺保护。最近在小鼠模型中发现， TNF超家族分子CD 153对肺结核感染具有部分保护作用（在IFNγ- 独立的方式）揭示了一种新的途径，潜在地确定一个重要的免疫相关的保护 结核分枝杆菌感染 在正在进行的实验中，我们发现来自潜伏性TB患者的Mtb特异性CD 4 + T细胞 感染（LTBI）表达CD 153，且该分子表达在患者中显著降低 活动性结核病此外，在有肺结核相关证据的无症状结核患者中， 使用PET/CT测量的炎症，Mtb特异性CD 4 T细胞中的CD 153表达与Mtb特异性CD 4 T细胞中的CD 153表达负相关。 有肺部代谢活动这些发现有力地表明，CD 153，沿着IFNg，可能需要 赋予最佳的保护以对抗人类的肺结核感染。 为了更好地了解CD 153（及其受体CD 30）在结核分枝杆菌保护中的作用，我们将：1） 全面表征潜伏性和活动性TB期间外周血中Mtb特异性CD 153 + CD 4 T细胞 2）确定HIV感染对Mtb特异性CD 4 T细胞表达的影响; ⑶ 153和3）研究⑶ 153/⑶ 30途径响应于Mtb的作用机制。 这项研究将1）增强我们对人类结核病保护所需的免疫机制的理解， 2)确定HIV感染改变这些免疫反应的新机制。该项目可能导致 开发新的工具来监测新型结核病疫苗的有效性。

PROJECT SUMMARY In 90% of cases, healthy persons infected with Mycobacterium tuberculosis (Mtb) remain asymptomatic. This implies that the host generates and maintains a partially protective immune response capable of containing bacterial replication. When this equilibrium is altered, such as during HIV-associated CD4 T cell depletion, TB disease can occur. However, the precise nature of Mtb-specific CD4+ T cells that confer immune protection remains elusive, hindering the development of new vaccines. It is now clearly established that while necessary, IFNγ is not sufficient to provide lung protection to Mtb. The recent finding, in a mouse model, that the TNF superfamily molecule CD153 confers partial protection for pulmonary Mtb infection (in an IFNγ- independent manner) reveals a new avenue to potentially identify an important immune correlate of protection to Mtb in humans. In ongoing experiments, we have found that Mtb-specific CD4+ T cells from individuals with latent TB infection (LTBI) express CD153 and that the expression of this molecule was significantly reduced in patients with active TB disease. Additionally, in TB asymptomatic persons with evidence of TB related lung inflammation measured using PET/CT, CD153 expression in Mtb-specific CD4 T cells negatively associates with lung metabolic activity. These findings strongly suggest that CD153, along with IFNg, may be required to confer optimal protection against pulmonary Mtb infection in humans. To better understand the role of CD153 (and its receptor, CD30) for Mtb protection, we will: 1) comprehensively characterize Mtb-specific CD153+ CD4 T cells during latent and active TB, both in peripheral blood and at sites of TB diseases; 2) define the impact of HIV infection on Mtb-specific CD4 T cells expressing CD153 and 3) investigate the mechanisms of action of the CD153/CD30 pathway in response to Mtb. This study will 1) enhance our understanding of immune mechanisms required for human TB protection and 2) identify novel mechanisms by which HIV infection alters these immune responses. This project could lead to the development of new tools to monitor the efficacy of novel TB vaccines.