Phenotypic and functional differences between wild-type and CCR2-/- dendritic cells:: Implications for islet transplantation
Phenotypic and functional differences between wild-type and CCR2-/- dendritic cells:: Implications for islet transplantation
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DOI：
10.1097/tp.0b013e31816843a0
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发表时间：
2008-04-15
期刊：
影响因子：
6.2
通讯作者：
Abdi, Reza
中科院分区：
文献类型：
--
作者：
Fiorina, Paolo;Jurewicz, Mollie;Abdi, Reza
背景树突状细胞（DC）是同种免疫反应的主要调节因子，其运输受趋化因子控制。在这里，我们提供的证据表明，CCR 2的缺乏可能会导致功能和表型不同的DC的产生，这可以部分解释在移植胰岛CCR 2（-/-）recipiers.Methods和结果的好处。我们表明，在体外DC成熟模型相反，在体内DC成熟伴随着CCR 2的表达增加。与野生型（WT）相比，从CCR 2（-/-）小鼠体外产生的DC，以及从CCR 2（-/-）幼稚小鼠或从CCR 2（-/-）胰岛同种异体移植受体中提取的DC，显示出较低的同种异体刺激能力。与WT DC相比，CCR 2（-/-）DC产生更多的IL-4，并诱导产生更多的IL-4的T细胞。CCR 2（-/-）DC还促进调节性T细胞的产生，所述调节性T细胞通过混合白细胞反应更有效地抑制T细胞增殖反应。同样，CCR 2（-/-）受体胰岛移植物中CD 4（+）CD 25（+）FoxP 3（+）细胞的百分比高于WT受体。总之，CCR 2的缺乏干扰了DC的同种异体刺激能力，并促进了调节性T细胞的产生。这是首次证明同种免疫中靶向特定趋化因子途径与DC调节T细胞轴之间存在机制联系。
Background. Trafficking of dendritic cells (DC), the primary regulators of alloimmune responses, is controlled by chemokines. Here, we provide evidence that lack of CCR2 could lead to the generation of functionally and phenotypically different DC, which in part could explain the benefits observed in transplanting islets in CCR2(-/-) recipients.Methods and Results. We show that, in contrast to the in vitro DC maturation model, in vivo DC maturation is accompanied by an increase in the expression of CCR2. Compared with wild-type (WT), DC generated in vitro from CCR2(-/-) mice, and DC extracted from CCR2(-/-) naive mice or from CCR2(-/-) recipients of islet allografts, display lesser allostimulatory capacity. Compared with WT DC, CCR2(-/-) DC produce more IL-4 and induce more IL-4-producing T cells. CCR2(-/-) DC also promote the generation of regulatory T cells that more efficiently suppress T cell proliferative responses by mixed leukocyte reaction. Similarly, the percentage of CD4(+)CD25(+)FoxP3(+) cells were found to be higher in CCR2(-/-) recipients of islet allografts than in WT recipients.Conclusions. In summary, lack of CCR2 interferes with the allostimulatory capacity of DC and promotes the generation of regulatory T cells. This is the first demonstration of a mechanistic link between targeting a specific chemokine pathway and the DC-regulatory T cell axis in alloimmunity.