Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions
Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions
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DOI：
10.1111/cei.12191
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发表时间：
2013-12-01
影响因子：
4.6
通讯作者：
Kwekkeboom, J.
中科院分区：
文献类型：
--
作者：
Boor, P. P. C.;Metselaar, H. J.;Kwekkeboom, J.
浆细胞样树突状细胞（PDC）通过产生干扰素（IFN）参与先天性免疫，并通过刺激T细胞和诱导产生调节性T细胞（T-reg）参与获得性免疫。在这项研究中，我们研究了雷帕霉素，一种常用的免疫抑制和抗癌药物，对人类PDC的先天性和适应性免疫功能的哺乳动物靶雷帕霉素（mTOR）抑制的影响。临床相关浓度的雷帕霉素有效地抑制Toll样受体（TLR）-7诱导的IFN-分泌（~ 64%），但TLR-9诱导的IFN-分泌仅轻微地抑制（~ 20%），而相同浓度抑制TLR-7活化的和TLR-9活化的PDC的促炎性细胞因子产生，具有相似的功效。雷帕霉素抑制TLR-7激活和TLR-9激活的PDC刺激同种异体T细胞产生IFN-γ和白细胞介素（IL）-10的能力。令人惊讶的是，mTOR抑制增强TLR-7激活的PDC刺激幼稚和记忆性T辅助细胞增殖的能力，这是由雷帕霉素诱导的PDC上CD 80表达上调引起的。最后，雷帕霉素处理TLR-7激活的PDC增强了它们诱导CD 4（+）叉头盒蛋白3（FoxP 3）（+）调节性T细胞的能力，但不影响抑制性CD 8（+）CD 38（+）淋巴细胞活化基因（LAG）-3（+）T（reg）的产生。一般而言，雷帕霉素抑制TLR刺激的人PDC的先天性和适应性免疫功能，但增强TLR-7刺激的PDC刺激CD 4（+）T细胞增殖和诱导CD 4（+）FoxP 3（+）调节性T细胞产生的能力。
Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)- production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (T-reg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN- secretion potently (-64%) but TLR-9-induced IFN- secretion only slightly (-20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN- and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4(+)forkhead box protein 3 (FoxP3)(+) regulatory T cells, but did not affect the generation of suppressive CD8(+)CD38(+)lymphocyte activation gene (LAG)-3(+)T(reg). In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4(+) T cell proliferation and induce CD4(+)FoxP3(+) regulatory T cell generation.