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

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是重要的，并且也参与肿瘤促进和进展。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。

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.