IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions
IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions
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DOI：
10.4049/jimmunol.178.1.271
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
More, Laurence
中科院分区：
文献类型：
--
作者：
Wan, Suigui;Xia, Changqing;More, Laurence
B6.Sle1.Sle2.Sle3三重同源小鼠（B6.TC）是在C57 BL/6背景上共表达三个主要NZM 2410衍生易感性基因座的狼疮模型。B6.TC小鼠产生高滴度的抗核肾源性自身抗体和高度渗透性肾小球肾炎。以前的研究表明，Sle 1基因座与调节性T细胞（Treg）数量减少有关，Sle 3导致髓样细胞的内在缺陷，从而过度激活T细胞。在这份报告中，我们发现B6.TC树突状细胞（DC）在淋巴器官中积累，并提出了一个有缺陷的成熟过程，其中骨髓源性，浆细胞样和髓样DC表达的CD 80，CD 86和MHC II类的水平显着降低。B6.TC DC还诱导比B6 DC更高水平的CD 4（+）T细胞增殖，并且B6.TC DC阻断Treg的抑制活性。B6.TC DC过度产生IL-6，这是阻断Treg活性所必需的，如抑制测定中抗IL-6中和Ab的作用所示。DC过度产生IL-6和阻断Treg活性映射到Sle 1，因此不仅赋予Treg数量减少，而且阻断其调节自身反应性T细胞的能力。两者合计，这些结果提供了一个遗传和机制的证据，系统性自身免疫性的调节性T细胞区室的数量和功能受损，并为Sle 1表达的DC发挥了重要作用，后者的缺陷，虽然他们的生产IL-6。
The B6.Sle1.Sle2.Sle3 triple congenic mouse (B6.TC) is a model of lupus coexpressing the three major NZM2410-derived susceptibility loci on a C57BL/6 background. B6.TC mice produce high titers of antinuclear nephrogenic autoantibodies and a highly penetrant glomerulonephritis. Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (Treg) and that Sle3 results in intrinsic defects of myeloid cells that hyperactivate T cells. In this report, we show that B6.TC dendritic cells (DCs) accumulate in lymphoid organs and present a defective maturation process, in which bone marrow-derived, plasmacytoid, and myeloid DCs express a significantly lower level of CD80, CD86, and MHC class II. B6.TC DCs also induce a higher level of proliferation in CD4(+) T cells than B6 DCs, and B6.TC DCs block the suppressive activity of Treg. B6.TC DCs overproduce IL-6, which is necessary for the blockade of Treg activity, as shown by the effect of anti-IL-6 neutralizing Ab in the suppression assays. The overproduction of IL-6 by DCs and the blockade of Treg activity maps to Sle1, which therefore not only confers a reduced number of Treg but also blocks their ability to regulate autoreactive T cells. Taken together, these results provide a genetic and mechanistic evidence for systemic autoimmunity resulting from an impaired regulatory T cell compartment in both number and function and for Sle1-expressing DCs playing a major role in the latter defect though their production of IL-6.