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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >CD4~+CD25~+Foxp3~+ regulatory T cells induce alternative activation of human monocytes/macrophages
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CD4~+CD25~+Foxp3~+ regulatory T cells induce alternative activation of human monocytes/macrophages

机译：CD4〜+ CD25〜+ Foxp3〜+调节性T细胞诱导人单核细胞/巨噬细胞的交替激活

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摘要

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 unchar-acterized function of Tregs, namely their ability to steer monocyte differentiation toward alternatively activated macrophages (AAM). AAM are cells with strong antiinflammatory 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 LPS in terms of proinflammatory mediator production (IL-1β, IL-6. IL-8, MIP-1α, TNF-α), NFκB 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.
机译：CD4〜+ CD25〜+ Foxp3〜+调节性T细胞（Tregs）是适应性免疫系统的有效抑制剂，但其对先天免疫细胞的作用尚不为人所知。在这里，我们证明了Tregs以前没有特征的功能，即它们引导单核细胞向交替激活的巨噬细胞（AAM）分化的能力。 AAM是具有强大抗炎潜能的细胞，参与免疫调节，组织重塑，杀死寄生虫和促进肿瘤。我们显示，与Tregs共培养后，单核细胞/巨噬细胞显示出AAM的典型特征，包括CD206（巨噬细胞甘露糖受体）和CD163（血红蛋白清除剂受体）的表达上调，CCL18的产量增加以及吞噬能力增强。此外，单核细胞/巨噬细胞在促炎性介质产生方面（IL-1β，IL-6，IL-8，MIP-1α，TNF-α）降低了HLA-DR的表达，并大大降低了对LPS的反应能力。 ，NFκB激活和酪氨酸磷酸化。机理研究表明，CD4〜+ CD25〜+ CD127〜（低）Foxp3〜+ Treg产生IL-10，IL-4和IL-13，而这些细胞因子是抑制促炎性细胞因子反应的关键因素。相反，Treg介导的CD206诱导完全不依赖细胞因子，而CD163，CCL18和吞噬作用的上调（部分）依赖于IL-10，而不依赖于IL-4 / IL-13。这些数据共同证明了CD4〜+ CD25〜+ Foxp3〜+ Treg以前无法识别的功能，即它们诱导单核细胞/巨噬细胞交替激活的能力。此外，数据表明，Treg介导的AAM诱导部分涉及一种新的，不依赖细胞因子的途径。

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