Th9 cells and protective TB immunity

Th9 细胞和保护性结核免疫

• 批准号: 10589125
• 负责人: Daniel F. Hoft
• 金额: $ 66.76万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-09 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589125
• 关键词: Adoptive Transfer; Affect; Allergic Reaction; BCG Vaccine; Bacille Calmette-Guerin vaccination; Bacteria; Blood; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cell physiology; Cells; Coculture Techniques; Data; Development; Disease; Genes; Genetically Engineered Mouse; Growth; Helminths; Human; Immune; Immunity; Immunotherapy; Infection prevention; Inflammation; Inflammatory; Interferons; Interleukin-4; Interleukin-9; Intravenous; Knockout Mice; Lung; Macaca; Macrophage; Mediating; Memory; Messenger RNA; Monocyte Chemoattractant Proteins; Mucous Membrane; Mus; Mycobacterium tuberculosis; Oral; Parasites; Patients; Peripheral Blood Mononuclear Cell; Persons; Play; Production; Proteins; RNA-Binding Proteins; Rag1 Mouse; Recombinants; Reporter; Reporting; Role; Route; Sampling; Source; T-Cell Activation; Testing; Th1 Cells; Transforming Growth Factor beta; Transgenic Mice; Tuberculosis; Tuberculosis Vaccines; Tumor Immunity; Vaccinated; Vaccinee; Vaccines; cell type; cytokine; healthy volunteer; human subject; improved; in vivo; indicated prevention; mycobacterial; novel; novel therapeutics; novel vaccines; protective effect; response; transcriptome; tuberculosis immunity; vaccine-induced immunity

-γ-producing Th1 cells have been extensively studied for development of novel vaccines and therapeutics against Mycobacterium tuberculosis (Mtb) infection. However, recent studies demonstrate that Mtb-specific Th1 cells alone do not predict protection against tuberculosis (TB). Therefore, although Th1 cells are required for controlling Mtb replication, other types of immune cells may be needed to prevent infection and eradicate the bacteria. We recently found that a subset of IL-9-producing CD4+ T cells (Th9) can mediate protective immunity against Mtb infection. Th9 cells can be differentiated from naïve CD4+ T cells with TGF-β and IL-4, and play important roles in antitumor immunity and immunity related to allergic reactions. The role of Th9 cells in Mtb infection, however, remain largely unknown. We discovered a role for Th9 cells in TB immunity when we analyzed the transcriptomes in CD4+ T cells from healthy volunteers vaccinated with BCG and from people with latent TB infection (LTBI). IL-9 mRNA in CD4+ T cells topped the list of genes increased after BCG vaccination and LTBI. A significant increase in IL-9 production by bronchoalveolar lavage (BAL) cells after stimulation with infectious Mtb was observed only in LTBI patients and people vaccinated with oral (PO) BCG, indicating induction of Mtb-specific Th9 memory responses. To test whether Th9 cells mediate intracellular Mtb killing, we differentiated Mtb-specific Th9 cells from ESAT6-TCR transgenic mice and co-cultured these Th9 cells with Mtb-infected murine macrophages. Intracellular mycobacterial growth was significantly reduced in macrophages after interacting with Th9 cells. Moreover, neutralizing IL-9 abolished the inhibitory effects of Th9 cells, while addition of recombinant IL-9 alone inhibited intracellular bacterial growth. Furthermore, adoptive transfer of Mtb-specific Th9 cells into syngeneic RAG1/2-/- mice suppresses Mtb growth in vivo. In addition, we found that IL-9 was increased and Mtb growth decreased in mice deficient in MCPIP1, a new RNA-binding protein affecting T cell activation. Deletion of MCPIP1 in Th9 cells resulted in a significantly enhanced IL-9 production upon restimulation. Based on our preliminary findings, we hypothesize that Mtb-specific Th9 cells represent a distinct subset of CD4+ T cells important for protective TB immunity. Strategies inducing Mtb- specific Th9 cells could be used to develop more effective TB vaccines and/or immunotherapies. We propose three aims to test this novel hypothesis: Aim 1 to determine the effects of Mtb-specific Th9 cells on protective TB immunity; Aim 2 to define the roles of IL-9 in vaccine-induced protection against Mtb infection using genetically engineered mice, and Aim 3 to identify the source for IL-9 in PBMC and BAL cells from BCG vaccinated individuals, and the mechanisms of Mtb-specific Th9 cell-mediated bacterial killing in human macrophages. These studies will have a significant impact on improving our understanding of host protective immune mechanisms against Mtb infection, and provide the rationale for targeting Mtb-specific Th9 cells as a new strategy for more effective TB vaccines and/or immunotherapies against Mtb infection.

已广泛研究了产生-γ的Th1细胞，用于开发新型疫苗和针对结核分枝杆菌（MTB）感染的治疗。但是，最近的研究表明，仅MTB特异性TH1细胞不能预测对结核病（TB）的保护。因此，尽管需要TH1细胞来控制MTB复制，但可能需要其他类型的免疫细胞来防止感染和放射性细菌。我们最近发现，产生IL-9的CD4+ T细胞的子集（TH9）可以介导受保护的免疫学针对MTB感染。 TH9细胞可以与具有TGF-β和IL-4的CD4+ T细胞区分开，并在与过敏反应有关的抗肿瘤免疫学和免疫学中起重要作用。但是，Th9细胞在MTB感染中的作用仍然很大程度上未知。当我们分析了来自BCG接种疫苗的健康志愿者和潜在结核病感染（LTBI）的患者的CD4+ T细胞中的转录组时，我们发现了TH9细胞在结核免疫学中的作用。 CD4+ T细胞中的IL-9 mRNA在BCG疫苗接种和LTBI后的基因列表升高。仅在LTBI患者中观察到了支气管肺泡灌洗（BAL）细胞的IL-9产生显着增加，而在LTBI患者中才观察到口服（PO）BCG接种的人，表明MTB特异性TH9记忆反应诱导。为了测试TH9细胞是否介质MTB杀伤，我们将MTB特异性TH9细胞与ESAT6-TCR转基因小鼠区分开，并将这些TH9细胞与MTB感染的鼠巨噬细胞共同培养。与TH9细胞相互作用后，巨噬细胞中细胞内分枝杆菌的生长显着降低。此外，中和IL-9消除了TH9细胞的抑制作用，而仅添加重组IL-9会抑制细胞内细菌的生长。此外，将MTB特异性TH9细胞的适应性转移到同烯rag1/2 - / - 小鼠中抑制了体内MTB的生长。此外，我们发现缺乏MCPIP1的小鼠的IL-9增加，MTB的生长降低，MCPIP1是一种影响T细胞激活的新的RNA结合蛋白。 TH9细胞中MCPIP1的缺失导致重新启动后的IL-9产生显着增强。根据我们的初步发现，我们假设MTB特异性TH9细胞代表了CD4+ T细胞的独特子集，对受保护的TB免疫史而言重要。策略引起的MTB特异性TH9细胞可用于开发更有效的TB疫苗和/或免疫疗法。我们提出了三个旨在检验这一新假设的目的：目的1确定MTB特异性TH9细胞对受保护的TB免疫力的影响； AIM 2使用一般工程的小鼠来定义IL-9在疫苗诱导的MTB感染中的作用，并瞄准3识别来自BCG疫苗接种个体中PBMC和BAL细胞中IL-9的来源，以及MTB特异性TH9细胞细胞介导的人类Mocrophage中MTB特异性TH9细胞介导的细菌的机制。这些研究将对我们对抗MTB感染的宿主受保护的免疫分布机制的理解产生重大影响，并为将MTB特异性TH9细胞靶向靶向MTB特异性TH9细胞提供了基本原理，作为对MTB感染更有效的TB疫苗和/或免疫疗法的新策略。