Ligand and cytokine dependence of the immunosuppressive pathway of tryptophan catabolism in plasmacytoid dendritic cells
Ligand and cytokine dependence of the immunosuppressive pathway of tryptophan catabolism in plasmacytoid dendritic cells
复制标题
DOI：
10.1093/intimm/dxh321
复制
发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
Puccetti, P
中科院分区：
文献类型：
--
作者：
Fallarino, F;Orabona, C;Puccetti, P
小鼠浆细胞样树突状细胞(PDC)在特定的环境中具有表达吲哚胺2，3-双加氧酶(IDO)功能和介导免疫抑制的独特能力；然而，自发和诱导活性的条件尚不清楚。我们利用已知的方法上调不同细胞类型的IDO，并研究了在脾pDC中诱导活性的相对有效性和机制，即CTLA-4-Ig、CD200-Ig或CD28-Ig与特异性受体结合后，后者结合细胞因子信号抑制物3(SOCS3)基因的沉默表达。我们发现PDCs(CD11c(+)mPDCA-1(+)120G8(+))在基础条件下不表达IDO并且不具有耐受性。在SOCS3缺陷的pDC中，CTLA-4-Ig结合B7-1、CD200-Ig结合CD200R1和CD28-Ig结合B7-1/B7-2均可通过不同机制启动IDO依赖耐受。干扰素-γ是CTLA-4-Ig效应的主要细胞因子，CD200-Ig的I型IFN是主要的细胞因子。在没有SOCS3的情况下，CD28-Ig对免疫的抑制需要干扰素-γ的诱导和IL-6的干扰素样作用。因此，尽管pDCs不是IDO依赖耐受的内在中介，但多个配体和细胞因子将有助于pDCs在小鼠体内表达一种耐受表型。
Murine plasmacytoid dendritic cells (pDCs) have been credited with a unique ability to express indoleamine 2,3-dioxygenase (IDO) function and mediate immunosuppression in specific settings; yet, the conditions of spontaneous versus induced activity have remained unclear. We have used maneuvers known to up-regulate IDO in different cell types and have examined the relative efficacy and mechanisms of the induced activity in splenic pDCs, namely, after specific receptor engagement by CTLA-4-Ig, CD200-Ig or CD28-Ig, the latter in combination with silenced expression of the suppressor of cytokine signaling 3 (SOCS3) gene. We found that pDCs (CD11c(+) mPDCA-1(+) 120G8(+)) do not express IDO and are not tolerogenic under basal conditions. B7-1 engagement by CTLA-4-Ig, CD200R1 engagement by CD200-Ig and B7-1/B7-2 engagement by CD28-Ig in SOCS3-deficient pDCs were each capable of initiating IDO-dependent tolerance via different mechanisms. IFN-gamma was the major cytokine responsible for CTLA-4-Ig effects, and type I IFNs for those of CD200-Ig. Immunosuppression by CD28-Ig in the absence of SOCS3 required IFN-gamma induction and IFN-like actions of IL-6. Therefore, although pDCs do not mediate IDO-dependent tolerance constitutively, multiple ligands and cytokines will contribute to the expression of a tolerogenic phenotype by pDCs in the mouse.