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.

一般认为，CD 4 + CD 25 + Foxp 3 + T细胞（TcB）抑制对微生物病原体的有效免疫。 在人类中，我们和其他人发现结核病患者中CD 4 + Foxp 3 + T细胞数量增加。我们还发现 在潜伏性结核病感染（LTBI）的患者中，结核分枝杆菌应答结核分枝杆菌而扩增。 结核分枝杆菌（Mtb），产生TGF-β和IL-10，并抑制CD 4+和CD 8+细胞产生IFN-γ，表明 它们可以限制组织炎症和破坏。然而，在人类中，一些活化的T细胞表达 Foxp 3瞬时表达，这些细胞缺乏经典的调节功能。最近我们发现了一个惊人的现象 来自LTBI患者的CD 4 + CD 25 + Foxp 3+细胞亚群抑制人结核分枝杆菌的生长， 单核细胞衍生的巨噬细胞（MDM）。一种可溶性因子，Rho GDP解离抑制剂（D4 GDI），产生 通过凋亡的CD 4 + CD 25 + Foxp 3 + D4 GDI+细胞导致这种对人结核分枝杆菌生长的抑制 巨噬细胞和小鼠。我们的研究提供了第一个证据，表明CD 4 + CD 25 + Foxp 3+亚群 细胞增强对M. tb，并确定了一种新的IFN-γ非依赖性，但T细胞依赖性机制 抑制了M结核菌在人巨噬细胞中的生长。该建议将确定D4 GDI在结核分枝杆菌中的作用 通过以下几个具体目标来实现。目标1.确定D4 GDI抑制 分枝杆菌生长。目标二。表征D4 GDI-产生FoxP 3+细胞的表型和功能， LTBI+个体和结核病患者。目标3.确定D4 GDI + Foxp 3+扩增的相关性 LTBI向活动性TB进展的可能性。

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