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

描述（由申请人提供）：我们已经确定了表达Foxp3的CD11b+F4/80+CD68+（巨噬细胞）的新群体。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、肝脏等组织中都有观察到。我们设计了一种利用Foxp3- gfp小鼠高度纯化CD11b+F4/80+Foxp3+巨噬细胞的策略。我们的研究结果表明，CD11b+F4/80+表达Foxp3的巨噬细胞抑制T细胞的增殖，而Foxp3阴性的巨噬细胞则没有。Foxp3pos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。CD11b+F4/80+Foxp3+细胞中Foxp3表达的消融导致其丧失抑制T细胞增殖的能力，证实Foxp3直接负责赋予巨噬细胞亚群抑制能力。Foxp3pos和Foxp3neg巨噬细胞的细胞因子和基因组图谱不同，表明这些细胞具有不同的生物学功能。此外，Foxp3pos巨噬细胞诱导新生转化Tregs，而Foxp3neg巨噬细胞则没有。功能分析表明CD11b+F4/80+Foxp3+巨噬细胞在诱导耐受性中起重要作用，并参与肿瘤的促进和进展。这些研究首次证明了天然巨噬细胞调节细胞（Mac-regs）的一个独特亚群的存在，其抑制功能与Foxp3的表达直接相关。综上所述，我们的初步结果导致我们假设CD11b+F4/80+Foxp3+细胞（Mac-regs）亚群是一个重要的调节细胞亚群，在调节免疫系统的稳态平衡中至关重要，这有助于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-regs抑制其他细胞的机制；目的2将评价Mac-regs诱导耐受的机制；而Aim 3将评估Mac-regs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.