Dendritic cell type determines the mechanism of bystander suppression by adaptive T regulatory cells specific for the minor antigen HA-1
Dendritic cell type determines the mechanism of bystander suppression by adaptive T regulatory cells specific for the minor antigen HA-1
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DOI：
10.4049/jimmunol.179.6.3443
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发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Burlingham, William J.
中科院分区：
文献类型：
--
作者：
Derks, Richard A.;Jankowska-Gan, Ewa;Burlingham, William J.
获得性耐受的一个标志是旁观者抑制，在这一过程中，Ag 特异性（适应性）T 调节细胞 (T-R) 抑制 T 效应细胞对特定 Ag 和共定位第三方 Ag 的反应。使用来自 HLA 相同肾移植受者的外周血 T 细胞作为体内延迟型超敏反应测定中的反应者，我们发现细胞 (DC)，而不是单核细胞 APC，可以介导 EBV 特异性回忆反应的旁观者抑制。当HA-I-H肽被添加到浆细胞样DC (pDC)和T细胞的混合物中时，旁观者对共定位回忆Ag的反应的抑制主要通过吲哚胺-2,3-双加氧酶(IDO)的产生而发生。类似地，在 T 细胞和 pDC 的共培养物中添加 HA-1(H) 肽，但不向髓样 DC (mDC) 中添加，可在体外诱导 IDO 活性。当 mDC 将 HA-1H 肽呈递给 Ag 特异性 CD8(+) TR 时，细胞因子释放（TGF-β、IL-10 或两者）是旁观者抑制的主要模式。通过 mDC 进行的旁观者抑制不仅可以被 TGF-β 及其 T 细胞受体抗体逆转，还可以被血小板反应蛋白-1 抗体逆转。在 T-DC 共培养物中添加 EBV 不会诱导 IDO 或血小板反应蛋白-1，这表明这些 DC 产物不是由效应 T 细胞诱导的，而仅由 TR 细胞诱导。这些结果揭示了器官移植耐受患者中供体 Ag 特异性 TR 的旁观者抑制机制，并强调了 mDC 和 pDC 在这一现象中的独特且关键的作用。
One hallmark of acquired tolerance is bystander suppression, a process whereby Ag-specific (adaptive) T regulatory cells (T-R) inhibit the T effector cell response both to specific Ag and to a colocalized third-party Ag. Using peripheral blood T cells from recipients of HLA-identical kidney transplants as responders in the trans vivo-delayed type hypersensitivity assay, we found that cells (DC), but not monocyte APCs, could mediate bystander suppression of EBV-specific recall response. When HA-I-H peptide was added to mixtures of plasmacytoid DC (pDC) and T cells, bystander suppression of the response to a colocalized recall Ag occurred primarily via indolamine-2,3-dioxygenase (IDO) production. Similarly, addition of HA-1(H) peptide to cocultures of T cells and pDC, but not myeloid DC (mDC), induced IDO activity in vitro. When mDC presented HA-1H peptide to Ag-specific CD8(+) TR, cytokine release (TGF-beta, IL-10, or both) was the primary mode of bystander suppression. Bystander suppression via mDC was reversed not only by Ab to TGF-beta and its receptor on T cells, but also by Ab to thrombospondin-1. EBV addition did not induce IDO or thrombospondin-1 in T-DC cocultures, suggesting that these DC products are not induced by T effector cells, but only by TR cells. These results shed light upon the mechanism of bystander suppression by donor Ag-specific TR in patients with organ transplant tolerance and underscores the distinct and critical roles of mDC and pDCs in this phenomenon.