Control of Transplant Tolerance and Intragraft Regulatory T Cell Localization by Myeloid-Derived Suppressor Cells and CCL5
Control of Transplant Tolerance and Intragraft Regulatory T Cell Localization by Myeloid-Derived Suppressor Cells and CCL5
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DOI：
10.4049/jimmunol.1101512
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发表时间：
2012-05-01
影响因子：
4.4
通讯作者：
Vanhove, Bernard
中科院分区：
文献类型：
--
作者：
Dilek, Nahzli;Poirier, Nicolas;Vanhove, Bernard
髓系来源的抑制细胞(MDSC)是一群异质性的未成熟细胞，被认为与调节性T细胞(Treg)有关，在癌症和器官移植的背景下抑制免疫反应。然而，MDSC与Treg的合作方式仍然难以捉摸。在这项研究中，我们使用DNA微阵列分析了来自异基因肾移植大鼠的血液来源的MDSC的基因表达。我们发现CCL5(RANTES)，一种趋化性C-C基序5趋化因子，在耐受方案治疗后被强烈下调。耐受组血浆中CCL5蛋白含量也较低，而移植肾内CCL5蛋白含量无明显变化。因为CCL5对Treg具有趋化作用，我们推测移植物和外周血之间的CCL5梯度可能有助于耐受动物的Treg在移植物内的定位。为了验证这一假设，我们用重组大鼠CCL5治疗肾移植耐受大鼠，以恢复正常的血浆浓度。这导致了通过免疫组织化学荧光和实时定量PCR检测Foxp3 mRNA的方法监测的移植物内Treg的显著减少。最终，这种治疗导致血清肌酐浓度增加，并在大约一个月后导致肾移植排斥反应。同基因移植物的肾功能不受类似剂量的CCL5的影响。这些数据突出了MDSC在耐受性肾移植受者中建立移植物到外周CCL5梯度的贡献，这控制了Treg在移植物中的招募，在移植物中可能有助于维持耐受性。免疫学杂志，2012,188：4209-4216。
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that are believed to inhibit immune responses in the contexts of cancer and organ transplantation, in association with regulatory T cells (Treg). However, the way in which MDSC cooperate with Treg remains elusive. In this study, we used DNA microarrays to analyze gene expression in blood-derived MDSC from rat recipients of kidney allografts. We found CCL5 (Rantes), a chemotactic C-C motif 5 chemokine, to be strongly downregulated after treatment with a tolerizing regimen. The amount of CCL5 protein was also lower in the plasma of tolerant recipients, whereas intragraft CCL5 was unchanged. Because CCL5 is chemotactic for Treg, we hypothesized that a gradient of CCL5 between the graft and peripheral blood might contribute to the intragraft localization of Treg in tolerant animals. To test this hypothesis, we treated tolerant rat recipients of kidney allografts with recombinant rat CCL5 to restore normal plasma concentrations. This led to a strong reduction in intragraft Treg monitored by immunohistofluorescence and by quantitative real-time PCR measurement of Foxp3 mRNA. Ultimately, this treatment led to an increase in serum creatinine concentrations and to kidney graft rejection after about a month. The kidney function of syngeneic grafts was not affected by a similar administration of CCL5. These data highlight the contribution of MDSC to the establishment of a graft-to-periphery CCL5 gradient in tolerant kidney allograft recipients, which controls recruitment of Treg to the graft where they likely contribute to maintaining tolerance. The Journal of Immunology, 2012, 188: 4209-4216.