IFN-γ independent inhibition of MTB growth in human macrophages

IFN-γ 独立抑制人巨噬细胞中 MTB 的生长

• 批准号: 9913448
• 负责人: Ramakrishna Vankayalapati
• 金额: $ 49.52万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-08 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913448
• 关键词: Activities of Daily Living; Adaptive Immune System; Allogenic; Alveolar Macrophages; Apoptosis; Apoptotic; Applications Grants; Autologous; Binding; CASP3 gene; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Nucleus; Cell physiology; Cells; Cessation of life; Cleaved cell; Cytokinesis; Data; Development; FOXP3 gene; Genes; Genus Mycobacterium; Growth; Guanine Nucleotide Dissociation Inhibitors; Household; Human; IL2RA gene; Immunity; Individual; Infection; Inflammation; Interferon Type II; Interferons; Interleukin-1 beta; Interleukin-10; Interleukin-6; Mediating; Mononuclear; Mus; Mycobacterium tuberculosis; Patients; Peripheral Blood Mononuclear Cell; Persons; Phagocytes; Phagocytosis; Phenotype; Physiological; Population; Production; Proteins; Publishing; Regulatory T-Lymphocyte; Role; Site; Surface; System; T-Lymphocyte; TNF gene; Testing; Tissues; Transforming Growth Factor beta; Tuberculosis; Vaccines; base; cell motility; cytokine; improved; macrophage; monocyte; mycobacterial; novel; pathogenic microbe; prevent; programmed cell death protein 1; promoter; response; rho; rho GTP-Binding Proteins; transcription factor

It is generally believed that CD4+CD25+Foxp3+ T-cells (Tregs) inhibit effective immunity to microbial pathogens. In humans, we and others have found increased numbers of CD4+Foxp3+ T-cells in TB patients. We also found that in persons with latent tuberculosis infection (LTBI), Tregs expand in response to Mycobacterium. tuberculosis (Mtb), produce TGF-β and IL-10 and inhibit IFN-γ production by CD4+ and CD8+ cells, suggesting that they may limit tissue inflammation and destruction. However, in humans, some activated T-cells express Foxp3 transiently and these cells lack classical regulatory function. Recently we made a surprising observation that a subpopulation of CD4+CD25+Foxp3+ cells from persons with LTBI inhibits growth of M.tb in human monocyte-derived macrophages (MDMs). A soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic CD4+CD25+ Foxp3+D4GDI+ cells is responsible for this inhibition of M.tb growth in human macrophages and in mice. Our study provides the first evidence that a subpopulation of CD4+CD25+Foxp3+ cells enhances immunity to M. tb, and identified a novel IFN-γ independent but T-cell dependent mechanism that inhibits M. tb growth in human macrophages. This proposal will determine the role of D4GDI in M.tb infection through the following specific aims. Aim 1. Determine the mechanisms by which D4GDI inhibit mycobacterial growth. Aim 2. Characterize the phenotype and function of D4GDI-producing FoxP3+ cells in LTBI+ individuals and tuberculosis patients. Aim 3. Determine the relevance of expansion of D4GDI+Foxp3+ cells to progression of LTBI to active TB.

通常认为CD4+CD25+FOXP3+T细胞（Tregs）抑制对微生物病原体的有效免疫学。 在人类中，我们和其他人发现TB患者中CD4+ FOXP3+ T细胞的数量增加。我们还发现 在患有潜在结核病感染（LTBI）的人中，Tregs响应分枝杆菌。 结核病（MTB），产生TGF-β和IL-10，并抑制CD4+和CD8+细胞产生的IFN-γ，这表明 它们可能会限制组织注射和破坏。但是，在人类中，一些激活的T细胞表达 FOXP3瞬时缺乏经典的调节功能。最近我们做了一个惊喜的观察 LTBI患者的CD4+CD25+FOXP3+细胞的亚群抑制了人类的M.TB的生长 单核细胞衍生的巨噬细胞（MDMS）。产生的实心因素，Rho GDP解离抑制剂（D4GDI） 由凋亡CD4+ CD25+ FOXP3+ D4GDI+细胞负责这种抑制人类的M.TB生长 巨噬细胞和小鼠。我们的研究提供了第一个证据，表明CD4+CD25+FOXP3+的亚群 细胞增强对M. tb的免疫力，并鉴定出一种新型的IFN-γ独立但依赖于T细胞的机制 这抑制了人类巨噬细胞中结核病的生长。该建议将确定D4GDI在M.TB中的作用 通过以下特定目标感染。目标1。确定D4GDI抑制的机制 分枝杆菌的生长。 AIM 2。表征D4GDI产生Foxp3+细胞的表型和功能 LTBI+个体和结核病患者。目标3。确定D4GDI+FOXP3+扩展的相关性 细胞向LTBI发展为活性TB。

项目成果

BCG vaccination reduces the mortality of Mycobacterium tuberculosis-infected type 2 diabetes mellitus mice.

BCG 疫苗接种可降低结核分枝杆菌感染的 2 型糖尿病小鼠的死亡率。

• DOI: 10.1172/jci.insight.133788
• 发表时间: 2020
• 期刊: JCI insight
• 影响因子: 8
• 作者: Radhakrishnan,RajeshKumar;Thandi,RamyaSivangala;Tripathi,Deepak;Paidipally,Padmaja;McAllister,MadelineKay;Mulik,Sachin;Samten,Buka;Vankayalapati,Ramakrishna
• 通讯作者: Vankayalapati,Ramakrishna