CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages
CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages
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DOI：
10.1073/pnas.0706832104
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发表时间：
2007-12-04
影响因子：
11.1
通讯作者：
Taams, Leonie S.
中科院分区：
文献类型：
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作者：
Tiemessen, Machteld M.;Jagger, Ann L.;Taams, Leonie S.
CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞（TCRs）是适应性免疫系统的有效抑制因子，但它们对先天免疫细胞的作用鲜为人知。在这里，我们证明了一个以前未表征的功能，即他们的能力，引导单核细胞分化为交替激活的巨噬细胞（AAM）。AAM是具有强抗炎潜力的细胞，参与免疫调节、组织重塑、寄生虫杀死和肿瘤促进。我们发现，与TMF共培养后，单核细胞/巨噬细胞显示AAM的典型特征，包括上调CD 206（巨噬细胞甘露糖受体）和CD 163（血红蛋白清道夫受体）的表达，增加CCL 18的产生，以及增强的吞噬能力。此外，单核细胞/巨噬细胞具有降低的HLA-DR表达和在促炎介质产生（IL-1 β、IL-6、IL-8、MIP-1 α、TNF-α）、NF κ B活化和酪氨酸磷酸化方面对LIPS的响应能力的强烈降低。机制研究表明，CD 4（+）CD 25（+）CD 127（低）Foxp 3（+）T细胞生成IL-10、IL-4和IL-13，这些细胞因子是参与抑制促炎细胞因子应答的关键因子。相反，Treg介导的CD 206诱导完全不依赖于亮氨酸，而CD 163、CCL 18和吞噬作用的上调（部分）依赖于IL-10，但不依赖于IL-4/IL-13。这些数据共同证明了CD 4（+）CD 25（+）Foxp 3（+）T细胞的一种以前未被认识的功能，即它们诱导单核细胞/巨噬细胞交替活化的能力。此外，这些数据表明，Treg介导的AAM诱导部分涉及一种新的，不依赖于精氨酸的途径。
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are potent suppressors of the adaptive immune system, but their effects on innate immune cells are less well known. Here we demonstrate a previously uncharacterized function of Tregs, namely their ability to steer monocyte differentiation toward alternatively activated macrophages (AAM). AAM are cells with strong anti inflammatory potential involved in immune regulation, tissue remodeling, parasite killing, and tumor promotion. We show that, after coculture with Tregs, monocytes/ macrophages display typical features of AAM, including up-regulated expression of CD206 (macrophage mannose receptor) and CD163 (hemoglobin scavenger receptor), an increased production of CCL18, and an enhanced phagocytic capacity. In addition, the monocytes/ macrophages have reduced expression of HLA-DR and a strongly reduced capacity to respond to LIPS in terms of proinflammatory mediator production (IL-1 beta, IL-6, IL-8, MIP-1 alpha, TNF-alpha), NF kappa B activation, and tyrosine phosphorylation. Mechanistic studies reveal that CD4(+)CD25(+)CD127(low)Foxp3(+) Tregs produce IL-10, IL-4, and IL-13 and that these cytokines are the critical factors involved in the suppression of the proinflammatory cytokine response. In contrast, the Treg-mediated induction of CD206 is entirely cytokine-independent, whereas the up-regulation of CD163, CCL18, and phagocytosis are (partly) dependent on IL-10 but not on IL-4/IL-13. Together these data demonstrate a previously unrecognized function of CD4(+)CD25(+) Foxp3(+) Tregs, namely their ability to induce alternative activation of monocytes/macrophages. Moreover, the data suggest that the Treg-mediated induction of AAM partly involves a novel, cytokine-independent pathway.