A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type IIFN signaling following B7 ligation
A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type IIFN signaling following B7 ligation
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DOI：
10.1093/intimm/dxh271
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发表时间：
2005-07-01
影响因子：
4.4
通讯作者：
Mellor, AL
中科院分区：
文献类型：
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作者：
Baban, B;Hansen, AM;Mellor, AL
通过连接CD 80/CD 86（B7）分子，合成的免疫调节剂CTLA 4-IG（可溶性合成CTLA 4融合蛋白）诱导吲哚胺2，3-双加氧酶（IDO）在一些树突状细胞（DC）中的表达，其结果是获得有效的T细胞调节功能。在这里，我们表明，这种反应只发生在一个人口的脾脏DC共表达的标志物CD 19。B7连接诱导分选的CD 19 + DC中转录因子信号转导子和转录激活子（STAT 1）的激活，但不诱导CD 19（NEG）DC中转录因子信号转导子和转录激活子（STAT 1）的激活。即使当DC缺乏II型IFN（IFN γ）的受体时，也发生STAT 1活化;然而，当DC缺乏I型IFN（IFN α β）的受体时，未观察到STAT 1活化和IDO上调。因此，IFN α而不是IFN γ信号传导对于B7连接后CD 19 + DC中的STAT 1活化和IDO上调是必需的。与这些发现一致，B7连接也诱导分选的CD 19 + DC而不是CD 19（NEG）DC表达IFN α。此外，重组IFN α诱导CD 19+而非CD 19（NEG）DC介导IDO依赖性T细胞抑制，表明IFN α信号传导可替代来自B7的上游信号。这些数据揭示了表达CD 19标记物的脾DC的少数群体独特地响应于B7连接，并且IFN α介导的STAT 1活化是促进这些DC中的IDO诱导的必要中间信号传导途径。因此，CD 19 + DC可能是表达表面CTLA 4的调节性T细胞的靶标，并且可以通过诱导IDO来抑制T细胞应答。
By ligating CD80/CD86 (B7) molecules, the synthetic immunomodulatory reagent CTLA4-Ig (soluble synthetic CTLA4 fusion protein) induces expression of the enzyme indoleamine 2,3-dioxygenase (IDO) in some dendritic cells (DCs), which acquire potent T cell regulatory functions as a consequence. Here we show that this response occurred exclusively in a population of splenic DCs co-expressing the marker CD19. B7 ligation induced activation of the transcription factor signal transducer and activator of transcription (STAT1) in sorted CD19+, but not CD19(NEG), DCs. STAT1 activation occurred even when DCs lacked receptors for type II IFN (IFN gamma); however, STAT1 activation and IDO up-regulation were not observed when DCs lacked receptors for type I IFN (IFN alpha beta). Thus, IFN alpha, but not IFN gamma, signaling was essential for STAT1 activation and IDO up-regulation in CD19+ DCs following B7 ligation. Consistent with these findings, B7 ligation also induced sorted CD19+, but not CD19(NEG), DCs to express IFN alpha. Moreover, recombinant IFN alpha induced CD19+, but not CD19(NEG), DCs to mediate IDO-dependent T cell suppression, showing that IFN alpha signaling could substitute for upstream signals from B7. These data reveal that a minor population of splenic DCs expressing the CD19 marker is uniquely responsive to B7 ligation, and that IFN alpha-mediated STAT1 activation is an essential intermediary signaling pathway that promotes IDO induction in these DCs. Thus, CD19+ DCs may be a target for regulatory T cells expressing surface CTLA4, and may suppress T cell responses via induction of IDO.