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.

- γ-对新型疫苗的发展和针对结核分枝杆菌（MTB）的疗法的发展。控制，可能需要其他类型的免疫细胞来预防和消除细菌。但是，TGF-β和IL-4 Lergic反应在MTB感染中的作用仍然很大潜在的TB感染（LTBI）CD4+中的IL-9 mRNA在BCG疫苗接种和LTBI之后增加了基因列表。测试TH9介导细胞内MTB杀死，我们将MTB特异性的Th9细胞与ESAT6-TCR转基因小鼠和培养基分化。中和IL-9废除了Th9细胞的抑制作用。在MCPIP1中，T TH9细胞中的MCPIP1的斜率在恢复时会显着增强IL-9的生产 - 特异性TH9细胞可用于开发更有效的TB疫苗和/或免疫疗法。 IL-9在疫苗诱导的对MTB感染的保护中使用遗传学的小鼠的作用，而AIM 3可以鉴定PBMC中IL-9的来源，而BAL细胞中的BLCG疫苗接种个体ELL介导的细菌杀死在人类巨噬细胞中具有显着改善我们对宿主保护性免疫机制的理解，并为将MTB特异性TH9细胞作为剂量的TEGY前疫苗和/或免疫疗法提供了针对MTB感染的有效的TEGE TH9细胞的基本原理。