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: 8106627
• 负责人: PETER A COHEN
• 金额: $ 37.58万
• 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/8106627
• 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. PUBLIC HEALTH RELEVANCE: For the first time we have identified a population of macrophages that express Foxp3. The Foxp3+ MX are able to inhibit the effector function of T cells. In vivo biological functions of Foxp3+ MX indicate that these induce immune tolerance and are important in promoting tumor growth. These results indicate that Foxp3+ MX are an important subset of regulatory cells critical in the homeostatic balance of the immune system. Learning more about the behavior of Foxp3+ MX is critical to understand the pathological function of these cells which could be related to tolerance, autoimmunity, tumor immunity, organ transplantation, allergy, and microbial immunity.

描述（由申请方提供）：我们已经鉴定了一种表达Foxp 3的新的CD 11b +F4/80+ CD 68+（巨噬细胞）群体。我们的初步结果表明，这些细胞在脾脏，淋巴结，骨髓，胸腺，外周血，肝脏和其他组织中观察到。我们设计了一种使用Foxp 3-GFP小鼠高度纯化CD 11b +F4/80+ Foxp 3+巨噬细胞的策略。我们的结果表明，表达Foxp 3的CD 11b +F4/80+巨噬细胞抑制T细胞的增殖，而Foxp 3阴性巨噬细胞没有。Foxp 3 pos巨噬细胞通过细胞：细胞接触机制或可溶性因子抑制T细胞增殖。CD 11b +F4/80+ Foxp 3+细胞上Foxp 3表达的消除导致其抑制T细胞增殖的能力丧失，证实Foxp 3直接负责赋予该巨噬细胞亚群抑制能力。Foxp 3 pos和Foxp 3 neg巨噬细胞的细胞因子和基因组谱是不同的，表明这些细胞具有不同的生物学功能。此外，Foxp 3 pos巨噬细胞诱导从头转化TcB，相反Foxp 3 neg巨噬细胞不诱导。功能分析表明CD 11b +F4/80+ Foxp 3+巨噬细胞对于耐受诱导很重要，并且也参与肿瘤的促进和进展。这些研究第一次证明了天然存在的巨噬细胞调节细胞（Mac-tumor）的不同亚群的存在，其中它们的抑制功能与Foxp 3的表达直接相关。综上所述，我们的初步结果导致假设CD 11b +F4/80+ Foxp 3+细胞（Mac-Foxp 3+）亚群是调节免疫应答的免疫系统的稳态平衡中至关重要的调节细胞的重要子集，所述免疫应答有助于T细胞耐受诱导和肿瘤促进/生长。为了验证我们的假设，将解决以下具体目标：目标1将定义Mac-R2抑制其他细胞的机制;目标2将评估Mac-R2诱导耐受的机制;目标3将评估Mac-R2在肿瘤促进和生长中的作用。 公共卫生相关性：我们首次发现了表达Foxp 3的巨噬细胞群体。Foxp 3 + MX能够抑制T细胞的效应子功能。Foxp 3 + MX的体内生物学功能表明，它们诱导免疫耐受并且在促进肿瘤生长中是重要的。这些结果表明，Foxp 3 + MX是免疫系统稳态平衡中至关重要的调节细胞的重要子集。了解更多关于Foxp 3 + MX的行为对于了解这些细胞的病理功能至关重要，这些细胞可能与耐受，自身免疫，肿瘤免疫，器官移植，过敏和微生物免疫有关。