PD-1-Mediated Suppression of IL-2 Production Induces CD8+ T Cell Anergy In Vivo
PD-1-Mediated Suppression of IL-2 Production Induces CD8+ T Cell Anergy In Vivo
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DOI：
10.4049/jimmunol.0900080
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
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作者：
Chikuma, Shunsuke;Terawaki, Seigo;Honjo, Tasuku
越来越多的证据表明，PD-1，一种在活化T细胞上表达的免疫抑制受体，调节外周T细胞耐受。特别是，PD-1参与诱导和/或维持T细胞对先前遇到的Ag的内在无反应性，尽管机制尚未确定。我们使用一个简单的实验模型来剖析建立无反应性的机制，其中通过单次注射同源肽使2C TCR转基因rag 2（-/-）PD-1（+/+）小鼠无反应。有趣的是，2C rag 2（-/-）PD-1（-/-）小鼠对相同处理的无反应性诱导完全耐受;因此，PD-1负责无反应性诱导。此外，PD-1表达在初始Ag暴露的24 It内诱导。无反应性的建立与CD 8（+）T细胞IL-2的显著下调有关。事实上，IL-2阻断甚至在2C rag 2（-/-）PD-1（-/-）T细胞中导致无反应性。此外，2C rag 2（-/-）PD-1（+/+）小鼠中IL-2信号的互补逆转了无反应性诱导。我们认为CD 8（+）T细胞无反应性是由细胞自主性IL-2合成的减少引起的，这是由PD-1对Ag刺激的快速表达以及随后周围细胞上的配体对该受体的刺激引起的。免疫学杂志，2009，182：6682-6689.
Accumulating evidence suggests that PD-1, an immuno-inhibitory receptor expressed on activated T cells, regulates peripheral T cell tolerance. In particular, PD-1 is involved in the induction and/or maintenance of T cells' intrinsic unresponsiveness to previously encountered Ags, although the mechanism is yet to be determined. We used a simple experimental model to dissect the mechanism for anergy establishment, in which 2C TCR transgenic rag2(-/-) PD-1(+/+) mice were anergized by a single injection of a cognate peptide. Interestingly, 2C rag2(-/-) PD-1(-/-) mice were totally resistant to anergy induction by the same treatment; thus, PD-1 was responsible for anergy induction. Furthermore, PD-1 expression was induced within 24 It of the initial Ag exposure. The establishment of anergy was associated with a marked down-regulation of IL-2 from the CD8(+) T cells. In fact, IL-2 blockade resulted in anergy even in 2C rag2(-/-)PD-1(-/-) T cells. Furthermore, the complementation of the IL-2 signal in 2C rag2(-/-)PD-1(+/+) mice reversed the anergy induction. We propose that CD8(+) T cell anergy is induced by a reduction of cell-autonomous IL-2 synthesis, which is caused by the quick expression of PD-1 in response to Ag stimulation and the subsequent stimulation of this receptor by its ligands on surrounding cells. The Journal of Immunology, 2009, 182: 6682-6689.