IFN-γ independent inhibition of MTB growth in human macrophages

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。 在人类中，我们和其他人发现结核病患者的CD4+Foxp3+T细胞数量增加。我们还发现 在潜伏性结核病感染(LTBI)患者中，Treg对分枝杆菌的反应会扩大。 结核，产生转化生长因子-β和IL-10，并抑制CD_4和CD_8+细胞产生干扰素-γ，提示 它们可以限制组织的炎症和破坏。然而，在人类中，一些激活的T细胞表达 Foxp3是暂时性的，这些细胞缺乏经典的调节功能。最近，我们进行了一项令人惊讶的观察 LTBI患者外周血中CD4+CD25+Foxp3+细胞亚群对结核分枝杆菌生长的抑制作用 单核细胞来源的巨噬细胞(MDM)。产生一种可溶性因子，Rho GDP解离抑制剂(D4GDI) 通过凋亡的CD4+CD25+Foxp3+D4GDI+细胞对人类结核分枝杆菌的生长产生抑制作用 巨噬细胞和小鼠体内。我们的研究提供了第一个证据，即CD4+CD25+Foxp3+亚群 细胞增强对结核分枝杆菌的免疫，并发现了一种新的干扰素-γ不依赖于T细胞的机制 这抑制了结核分枝杆菌在人类巨噬细胞中的生长。本提案将确定D4GDI在结核分枝杆菌中的作用 通过以下具体目标感染。目的1.确定D4GDI抑制的机制 分枝杆菌的生长。目的2.鉴定产生D4GDI的FoxP3+细胞的表型和功能。 LTBI阳性者和结核病患者。目的3.确定D4GDI+Foxp3+扩增的相关性 细胞从LTBI进展为活动性结核。

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.