Role of Macrophage Regulatory Cells (Mac-regs) in Immune Regulation

巨噬细胞调节细胞 (Mac-regs) 在免疫调节中的作用

• 批准号: 8309017
• 负责人: PETER A COHEN
• 金额: $ 41万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309017
• 关键词: Ablation; Address; Animals; Autoimmunity; Behavior; Biological; Biological Process; Bone Marrow; Cell physiology; Cells; Data; Development; Disease; Equilibrium; Genomics; Goals; Growth; Hypersensitivity; ITGAM gene; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Lead; Learning; Liver; Mediating; Metastatic Lesion; Mus; Organ Transplantation; Population; Primary Neoplasm; Regulation; Role; Spleen; Staging; T-Cell Proliferation; T-Lymphocyte; Testing; Thymus Gland; Time; Time Study; Tissues; Tumor Immunity; Tumor Promotion; base; cytokine; design; in vivo; insight; lymph nodes; macrophage; microbial; neoplastic cell; oral tolerance; peripheral blood; prevent; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): We have identified a new population of CD11b+F4/80+CD68+ (macrophages) that express Foxp3. Our initial results indicate that these cells were observed in spleen, lymph nodes, bone marrow, thymus, peripheral blood, liver and other tissues. We devised a strategy to highly purify CD11b+F4/80+Foxp3+ macrophages using the Foxp3-GFP mice. Our results show that CD11b+F4/80+ macrophages expressing Foxp3 inhibited the proliferation of T cells whereas Foxp3neg macrophages did not. Foxp3pos macrophages inhibited the proliferation of T cells through cell: cell contact mechanisms or soluble factors. Ablation of Foxp3 expression on CD11b+F4/80+Foxp3+ cells results in their lost capacity to inhibit the proliferation of T cells confirming that Foxp3 is directly responsible for conferring suppressive capabilities to this subpopulation of macrophages. The cytokine and genomic profiles of Foxp3pos and Foxp3neg macrophages were distinctive indicating that these cells have different biological functions. Furthermore, Foxp3pos macrophages induce de novo conversion Tregs, in contrast Foxp3neg macrophages did not. Functional analysis indicated that CD11b+F4/80+Foxp3+ macrophages are important for tolerance induction and are involved as well in tumor promotion and progression. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells (Mac-regs) in which their suppressive function is directly correlated to the expression of Foxp3. Taken together our preliminary results lead to hypothesize that CD11b+F4/80+Foxp3+ cells (Mac-regs) subpopulation is an important subset of regulatory cells critical in the homeostatic balance of the immune system regulating immune responses which contribute to T cell tolerance induction and tumor promotion/growth. In order to test our hypothesis the following specific aims will be addressed: Aim 1 will define the mechanisms by which Mac-regs inhibit other cells; Aim 2 will evaluate the mechanism of tolerance induction by Mac-regs; and Aim 3 will evaluate the role of Mac-regs in tumor promotion and growth.

描述（由申请人提供）：我们已经确定了表达FOXP3的新的CD11b+F4/80+CD68+（巨噬细胞）的新种群。我们的最初结果表明，这些细胞是在脾脏，淋巴结，骨髓，胸腺，外周血，肝脏和其他组织中观察到的。我们设计了一种使用FOXP3-GFP小鼠高度净化CD11B+F4/80+FOXP3+巨噬细胞的策略。我们的结果表明，表达FOXP3的CD11b+ F4/80+巨噬细胞抑制了T细胞的增殖，而Foxp3neg巨噬细胞没有。 FOXP3POS巨噬细胞通过细胞抑制了T细胞的增殖：细胞接触机制或可溶性因子。 FOXP3表达在CD11b+F4/80+FOXP3+细胞上的消融导致其抑制T细胞增殖的能力丧失，证实FOXP3直接负责赋予抑制能力以使巨噬细胞的亚群体造成抑制能力。 FOXP3POS和FOXP3NEG巨噬细胞的细胞因子和基因组谱图表明这些细胞具有不同的生物学功能。此外，FOXP3POS巨噬细胞诱导从头转换Tregs，相反，Foxp3neg巨噬细胞没有。功能分析表明，CD11b+F4/80+FOXP3+巨噬细胞对于耐受性诱导很重要，并且还参与了肿瘤促进和进展。这些研究首次证明了天然存在的巨噬细胞调节细胞（MAC-REGS）的独特亚群，其中它们的抑制功能与Foxp3的表达直接相关。总而言之，我们的初步结果导致假设CD11b+F4/80+FOXP3+细胞（MAC-REGS）亚群是调节细胞的重要子集，这对调节免疫反应的稳态平衡至关重要，从而导致T细胞耐受性诱导和肿瘤促进和肿瘤的促进/生长/生长。为了检验我们的假设，将解决以下特定目标：AIM 1将定义MAC-REG抑制其他细胞的机制； AIM 2将评估MAC-REGS耐受性诱导的机制； AIM 3将评估MAC-REG在肿瘤促进和生长中的作用。