Chiang Po-Hui, Wang Lianfu, Bonham C Andrew, Liang Xiaoyan, Fung John J, Lu Lina, Qian Shiguang
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
J Immunol. 2004 Feb 1;172(3):1355-63. doi: 10.4049/jimmunol.172.3.1355.
The suppressive effect of rapamycin on T cells has been extensively studied, but its influence on the function of APC is less clear. The data in this study demonstrated that immunostimulatory activity of B10 (H2(b)) dendritic cells (DC) exposed to rapamycin (rapa-DC) was markedly suppressed as evidenced by the induction of low proliferative responses and specific CTL activity in allogeneic (C3H, H2(k)) T cells. Administration of rapa-DC significantly prolonged survival of B10 cardiac allografts in C3H recipients. Treatment with rapamycin did not affect DC expression of MHC class II and costimulatory molecules or IL-12 production. Rapamycin did not inhibit DC NF-kappaB pathway, however, IL-12 signaling through Janus kinase 2/Stat4 activation was markedly suppressed. Indeed, Stat4(-/-) DC similarly displayed poor allostimulatory activity. The Stat4 downstream product, IFN-gamma, was also inhibited by rapamycin, but DC dysfunction could not solely be attributed to low IFN-gamma production as DC deficient in IFN-gamma still exhibited vigorous allostimulatory activity. Rapamycin did not affect DC IL-12R expression, but markedly suppressed IL-18Ralpha and beta expression, which may in turn down-regulate DC IL-12 autocrine activation.
雷帕霉素对T细胞的抑制作用已得到广泛研究，但其对抗原呈递细胞（APC）功能的影响尚不清楚。本研究中的数据表明，暴露于雷帕霉素的B10（H2(b)）树突状细胞（DC）（雷帕霉素处理的DC，rapa-DC）的免疫刺激活性受到显著抑制，这可通过在同种异体（C3H，H2(k)）T细胞中诱导低增殖反应和特异性细胞毒性T淋巴细胞（CTL）活性来证明。给予rapa-DC可显著延长C3H受体中B10心脏同种异体移植物的存活时间。雷帕霉素处理不影响DC的MHC II类分子和共刺激分子的表达或IL-12的产生。雷帕霉素不抑制DC的NF-κB信号通路，然而，通过Janus激酶2/信号转导和转录激活因子4（Stat4）激活的IL-12信号传导受到显著抑制。事实上，Stat4基因敲除的DC同样表现出较弱的同种异体刺激活性。雷帕霉素也抑制Stat4的下游产物γ干扰素（IFN-γ），但DC功能障碍不能完全归因于IFN-γ产生减少，因为缺乏IFN-γ的DC仍表现出强烈的同种异体刺激活性。雷帕霉素不影响DC的IL-12受体表达，但显著抑制IL-18Rα和β的表达，这可能进而下调DC的IL-12自分泌激活。
