Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8+ T cells produce active immune unresponsiveness
Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8+ T cells produce active immune unresponsiveness
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DOI：
10.4049/jimmunol.168.11.5589
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发表时间：
2002-06-01
影响因子：
4.4
通讯作者：
Green, DR
中科院分区：
文献类型：
--
作者：
Ferguson, TA;Herndon, J;Green, DR
通过静脉注射抗原偶联的淋巴细胞诱导免疫无反应性已被广泛研究，但其机制仍不清楚。我们通过检测Fas/Fas配体（FasL）介导的细胞凋亡的作用进一步探索了该模型。利用静脉注射三硝基苯基偶联的脾细胞（TNP - spl）作为耐受原，我们发现由受体中的FasL传递的针对脾细胞凋亡的Fas信号是关键事件。通过预先诱导TNP - spl中的细胞凋亡可克服对Fas和FasL的需求，使耐受原的效力提高100倍。半胱天冬酶抑制剂阻止细胞凋亡可阻断耐受。有趣的是，虽然阻断CD40/CD40配体相互作用并不妨碍耐受诱导，但一种激动性抗CD40抗体可将致耐受的TNP - spl转变为免疫原性抗原。研究进一步表明，耐受是通过CD8(+)CD11c(+)淋巴细胞衍生的树突状细胞以I类主要组织相容性复合体（MHC）依赖的方式交叉呈递抗原给调节性T细胞而诱导的。这些结果为一种已确立的诱导免疫无反应性的方法提供了一种机制。
The induction of immunologic unresponsiveness by i.v. administration of Ag-coupled lymphoid cells has been studied extensively, but the mechanisms remain unclear. We have further explored this model by examining the role of Fas/Fas ligand (FasL)-mediated apoptosis. Using i.v. injection of trinitrophenyl-coupled splenocytes (TNP-spl) as tolerogen, we found that Fas signaling for apoptosis in the spleen cells delivered by FasL in the recipient is the critical event. The requirement for Fas and FasL was overcome by prior induction of apoptosis in TNP-spl, making the tolerogen 100 times more potent. Prevention of apoptosis by a caspase inhibitor blocks tolerance. Interestingly, while blocking CD40/CD40 ligand interaction does not prevent tolerance induction, an agonist anti-CD40 Ab turns tolerogenic TNP-spl into an immunizing Ag. Studies further showed that tolerance is induced through cross-presentation of Ag in a class I MHC-dependent manner by CD8(+)CD11c(+) lymphoid-derived dendritic cells to regulatory T cells. The results provide a mechanism for a well-established method of inducing immunologic unresponsiveness.