Intrarenal antigens activate CD4+ cells via co-stimulatory signals from dendritic cells
Intrarenal antigens activate CD4+ cells via co-stimulatory signals from dendritic cells
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DOI：
10.1681/asn.2007030386
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发表时间：
2008-03-01
影响因子：
13.6
通讯作者：
Kitching, A. Richard
中科院分区：
文献类型：
--
作者：
Edgtton, Kristy L.;Kausman, Joshua Y.;Kitching, A. Richard
肾中的树突状细胞吸收抗原，但对它们在为CD4（+）细胞的激活提供共刺激信号方面的作用知之甚少。本研究检测了肾内卵清蛋白注射前后肾间质和肾引流淋巴结中树突状细胞的表型。肾内注射抗原后，共刺激分子CD86和程序性细胞死亡配体1 （PD-L1）在肾树突状细胞上的表达增加，而在引流淋巴结的树突状细胞上仅CD86的表达增加。在给药前，通过将荧光标记的卵清蛋白特异性T细胞受体转基因细胞转移到小鼠体内，评估淋巴结中抗原特异性CD4（+）细胞的活化和增殖。阻断CD86和CD80均可显著抑制CD4（+）细胞的增殖，但CD86是CD4（+）细胞早期增殖反应中的显性CD28配体。相反，PD-1的激活，CD4（+）细胞上表达的结合PD-L1和PD-L2的受体，减少了引流淋巴结中CD4（+）细胞的增殖。对比皮下和肾内给抗原，发现经肾给抗原比经皮肤给抗原激活CD4（+）细胞更慢，CD80和CD86联合阻断的效果更深刻。总之，肾树突状细胞摄取抗原，并通过上调共刺激分子（如CD86）刺激CD4（+）细胞增殖，并通过PD-1信号传导，从而阻止不适当的旺盛免疫反应，参与抗原特异性CD4（+）细胞增殖的控制。
Dendritic cells in the kidney take up antigens, but little is known about their role in providing costimulatory signals for the activation of CD4(+) cells. This study examined the phenotype of dendritic cells in the renal interstitium and in the lymph node draining the kidney before and after intrarenal ovalbumin injection. After intrarenal injection of the antigen, expression of the co-stimulatory molecules CD86 and programmed cell death ligand 1 (PD-L1) increased on renal dendritic cells, whereas expression of only CD86 increased on dendritic cells of the draining lymph node. The activation and proliferation of antigen-specific CD4(+) cells in the lymph node were assessed by transfer of naive, fluorescently labeled ovalbumin-specific T cell receptor transgenic cells to mice before antigen administration. Blocking both CD86 and CD80 profoundly inhibited CD4(+) cell proliferation, but CD86 was the dominant CD28 ligand in the early proliferative response of CD4(+) cells. Conversely, activation of PD-1, the receptor expressed on CD4(+) cells that binds PD-L1 and PD-L2, reduced the proliferation of CD4(+) cells in the draining lymph node. Comparing subcutaneous and intrarenal administration of antigen, it was found that CD4(+) cell activation was slower and the effects of combined CD80 and CD86 blockade were more profound when antigen was presented via the kidney compared with the skin. In summary, renal dendritic cells take up antigen and participate in the control of antigen-specific CD4(+) cell proliferation by upregulating co-stimulatory molecules such as CD86 that stimulate CD4(+) cell proliferation and by signaling through PD-1, which prevents an inappropriately exuberant immune response.