Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA
Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA
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DOI：
10.1093/intimm/dxh255
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Hughes, CCW
中科院分区：
文献类型：
--
作者：
Mestas, J;Crampton, SP;Hughes, CCW
人内皮细胞（EC）组成性表达OX 40 L并共刺激依赖于OX 40-OX 40 L相互作用的记忆性CD 4（+）T细胞增殖。在体内，OX 40抑制T细胞存活;然而，一个未回答的问题是它是否也可以延长增殖维持细胞因子如IL-2的合成。在这里，我们表明EC共刺激导致T细胞IL-2，IL-3和IFN-γ的分泌，并且在不存在OX 40信号的情况下，合成在12-18小时内基本停止，但在OX 40信号的存在下延长至60小时。随后阻断OX 40介导的细胞因子表达会抑制T细胞增殖，这可以通过添加外源性IL-2来克服。我们发现，OX 40信号传导对T细胞活化具有离散效应，因为它不影响IL-10、CD 25、CD 69或可溶性IL-2 R的表达。此外，OX 40似乎并不改变IL-2的转录，而是起到稳定细胞因子mRNA亚群的作用，使其半衰期增加3-6倍。我们进一步表明，OX 40 L诱导T细胞中p38丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶（PI 3 K）的活化，并且使用特异性抑制剂，我们发现增加的mRNA半衰期依赖于这两种途径，但不依赖于c-jun-N-末端激酶（JNK）。因此，EC通过OX 40共刺激导致T细胞细胞因子合成延长和增殖增强。
Human endothelial cells (ECs) constitutively express OX40L and co-stimulate memory CD4(+) T cell proliferation that is dependent upon OX40-OX40L interaction. In vivo, OX40 prolongs T cell survival; however, an unanswered question is whether it can also prolong synthesis of proliferation-sustaining cytokines such as IL-2. Here we show that EC co-stimulation results in the secretion of T cell IL-2, IL-3 and IFN-gamma and that in the absence of OX40 signals synthesis largely ceases by 12-18 h, but is prolonged up to 60 h in the presence of OX40 signaling. Blocking OX40-mediated cytokine expression at later times suppresses T cell proliferation and this can be overcome by addition of exogenous IL-2. We find that OX40 signaling has discrete effects on T cell activation as it does not affect expression of IL-10, CD25, CD69 or soluble IL-2R. Also, OX40 does not appear to alter IL-2 transcription, but rather acts to stabilize a subset of cytokine mRNAs, increasing their half-lives by 3-6-fold. We further show that OX40L induces activation of p38 mitogen-activated protein kinase (MAPK) and phosphotidyl-inositol-3-kinase (PI3K) in T cells, and using specific inhibitors, we find that increased mRNA half-life is dependent upon both these pathways but is independent of c-jun-N-terminal kinase (JNK). Thus, EC co-stimulation through OX40 leads to prolonged T cell cytokine synthesis and enhanced proliferation.