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

结核病免疫中 CD4 Th 亚群的多样性 - HIV 感染的影响

• 批准号: 8989972
• 负责人: Catherine Riou
• 金额: $ 21.19万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989972
• 关键词: Activities of Daily Living; CD4 Positive T Lymphocytes; Cell Lineage; Cell physiology; Cells; Characteristics; Communicable Diseases; Containment; Country; Defect; Development; Disease; Disease Progression; Epidemic; Equilibrium; Event; Exhibits; Flow Cytometry; Genetic Transcription; Genus Mycobacterium; HIV; HIV Infections; Health; Helper-Inducer T-Lymphocyte; Immune; Immune response; Individual; Infection; Infection Control; Influentials; Intervention; Knowledge; Lead; Maintenance; Molecular Profiling; Mycobacterium Infections; Mycobacterium tuberculosis; Natural Immunity; Nature; Pathogenesis; Pattern; Phase; Predisposition; Regulatory T-Lymphocyte; Research Personnel; Risk; Risk Factors; South Africa; T cell differentiation; T cell response; Testing; Tuberculosis; base; flexibility; immune activation; insight; memory CD4 T lymphocyte; novel; programs; research study; response; transcription factor; tuberculosis immunity

 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.

 描述（由研究者提供）：在90%的病例中，感染结核分枝杆菌（Mtb）的健康个体保持无症状。这意味着宿主产生并维持能够抑制细菌复制的部分保护性免疫应答。当这种平衡被改变时，结核病就可能发生。除了先天免疫的参与外，有效的TB免疫应答还取决于CD4+ T细胞。艾滋病毒是结核病的主要危险因素之一，改变结核病免疫反应，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细胞的大量耗竭。然而，结核病的风险在艾滋病毒感染后不久就增加了，在严重的CD4损失发生之前。这表明HIV也可能诱导CD4+ T细胞功能的质的变化，削弱保护性TB免疫应答。然而，赋予免疫保护的分枝杆菌特异性CD4+ T细胞的确切性质仍然难以捉摸。因此，至关重要的是定义参与Mtb潜伏期建立的CD4+ T辅助细胞亚群的类型和平衡，并确定HIV在多大程度上甚至在免疫活性个体中扰乱这种平衡。 在正在进行的实验中，我们已经发现，结核分枝杆菌特异性的CD4+ T细胞从潜伏性结核感染（LTBI）的个人表现出不同的平衡的辅助性T细胞亚群，其特征是共表达的谱系定义的转录因子。重要的是，我们已经发现，在分枝杆菌特异性CD4+ T细胞中的这些单细胞转录共表达模式受到HIV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CD4+ T细胞应答是针对持续TB遏制所需的CD4+ T辅助细胞亚群的特定平衡而定制的，但是HIV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，使用基于转录和流式细胞术的方法，我们提出了以下具体目标：1）确定分枝杆菌特异性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性和活动性结核病患者中是否不同，2）测试HIV感染如何改变 分枝杆菌特异性CD4+ T细胞的转录因子共表达模式、谱系定型和转录程序。 我们预计这项研究将：1）揭示分枝杆菌特异性CD4+ T细胞谱系定型的复杂性和灵活性，2）确定HIV感染改变这些免疫反应的新机制。该项目将导致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。

项目成果

Selective reduction of IFN-γ single positive mycobacteria-specific CD4+ T cells in HIV-1 infected individuals with latent tuberculosis infection.

• DOI: 10.1016/j.tube.2016.07.018
• 发表时间: 2016-12
• 期刊: Tuberculosis (Edinburgh, Scotland)
• 作者: Riou C;Bunjun R;Müller TL;Kiravu A;Ginbot Z;Oni T;Goliath R;Wilkinson RJ;Burgers WA
• 通讯作者: Burgers WA

Effect of HIV on the Frequency and Number of Mycobacterium tuberculosis-Specific CD4+ T Cells in Blood and Airways During Latent M. tuberculosis Infection.

• DOI: 10.1093/infdis/jix529
• 发表时间: 2017-12-19
• 期刊: The Journal of infectious diseases
• 作者: Bunjun R;Riou C;Soares AP;Thawer N;Müller TL;Kiravu A;Ginbot Z;Oni T;Goliath R;Kalsdorf B;von Groote-Bidlingmaier F;Hanekom W;Walzl G;Wilkinson RJ;Burgers WA
• 通讯作者: Burgers WA