Diversity of CD4+ Th subsets in TB immunity - Impact of HIV infection

 描述(由调查人员提供)：在90%的病例中，感染结核分枝杆菌(Mtb)的健康人仍然没有症状。这意味着宿主产生并维持一种能够遏制细菌复制的部分保护性免疫反应。当这种平衡被改变时，结核病就会发生。除了先天免疫的参与，有效的结核病免疫反应还依赖于CD4+T细胞。艾滋病毒是结核病的主要风险因素之一，它改变了结核病的免疫反应，使其发展为活动性结核病。HIV感染引起的最明显的免疫缺陷是CD4+T细胞的大量耗尽。然而，在HIV感染后不久，在发生严重的CD4丢失之前，结核病的风险就会增加。这表明HIV还可能导致CD4+T细胞功能发生质的变化，从而削弱保护性结核病免疫反应。然而，分枝杆菌特异性的CD4+T细胞提供免疫保护的确切性质仍然难以捉摸。因此，确定参与MTB潜伏期建立的CD4+T辅助细胞亚群的类型和平衡，并确定即使在具有免疫能力的个体中，HIV对这种平衡的干扰程度也是至关重要的。在正在进行的实验中，我们发现来自潜伏性结核病感染(LTBI)患者的分枝杆菌特异性CD4+T细胞表现出T辅助细胞亚群的多样化平衡，其特征是谱系定义转录因子的共同表达。重要的是，我们已经发现，分枝杆菌特异性CD4+T细胞中的这些单细胞转录共表达模式受到艾滋病毒感染的显著干扰。鉴于这些发现，我们假设在健康个体中，分枝杆菌特异性的CD4+T反应是针对持续控制结核病所需的CD4+T辅助细胞亚群的特定平衡而定制的，但艾滋病毒感染破坏了这种CD4+T细胞分化平衡的建立或维持。为了验证这一假设，使用全局转录和基于流式细胞术的方法，我们提出了以下具体目标：1)定义分枝杆菌特异性CD4+T细胞中辅助性T细胞分化的谱，并测试这种模式在潜伏期和活动性肺结核患者中是否不同，以及2)测试HIV感染如何改变 分枝杆菌特异性CD4+T细胞转录因子共表达模式、谱系承诺和转录程序。我们预计，这项研究将：1)揭示分枝杆菌特异性CD4+T细胞谱系承诺的复杂性和灵活性；2)确定HIV感染改变这些免疫反应的新机制。该项目将有助于更好地了解结核病的免疫保护机制，从而对结核病的免疫干预产生影响。

 DESCRIPTION (provided by investigator): In 90% of cases, healthy individuals 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, TB disease can occur. Besides the involvement of innate immunity, an efficient TB immune response also depends on CD4+ T cells. HIV is one of the major risk factors for TB, altering TB immune responses allowing progression to active TB. The most obvious immune defect induced by HIV infection is a massive depletion of CD4+ T cells. However, the risk of TB is increased soon after HIV infection, before profound CD4 loss occurs. This suggests that HIV may also induce qualitative changes in CD4+ T cell function, weakening protective TB immune responses. However, the precise nature of mycobacteria-specific CD4+ T cells that confer immune protection remains elusive. It is therefore of crucial importance to define the type and balance of CD4+ T helper subsets that participate in the establishment of Mtb latency, and establish to what extent HIV disturbs this equilibrium even in immuno- competent individuals. In ongoing experiments, we have found that mycobacteria-specific CD4+ T cells from individuals with latent TB infection (LTBI) exhibit a diverse balance of T helper subsets, characterized by the co-expression of lineage-defining transcription factors. Importantly, we have found that these single-cell transcription co- expression patterns in mycobacteria-specific CD4+ T cells are dramatically perturbed by HIV infection. Given these findings, we hypothesize that in healthy individuals, mycobacteria-specific CD4+ T responses are tailored towards a particular balance of CD4+ T helper cell subsets required for ongoing TB containment, but that HIV infection derails the establishment or maintenance of this CD4+ T cell differentiation balance. To test this hypothesis, using both global transcriptional and flow cytometry-based approaches, we propose the following specific aims: 1) To define the spectrum of T helper differentiation in mycobacteria- specific CD4+ T cells and test whether this pattern differs in individuals with latent and active tuberculosis, and 2) to test how HIV infection alters the transcription factor co-expression pattern, lineage commitment and transcriptional program of mycobacteria-specific CD4+ T cells. We anticipate that this study will: 1) reveal the complexity and flexibility of mycobacteria-specific CD4+ T cell lineage commitment and 2) identify novel mechanisms by which HIV infection alters these immune responses. This project will lead to a better understanding of immune mechanisms of protection against TB and thus be influential in immune intervention against TB.