Activation of NF-κB1 by OX40 contributes to antigen-driven T cell expansion and survival
Activation of NF-κB1 by OX40 contributes to antigen-driven T cell expansion and survival
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DOI：
10.4049/jimmunol.180.11.7240
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Croft, Michael
中科院分区：
文献类型：
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作者：
Song, Jianxun;So, Takanori;Croft, Michael
共刺激分子OX40(CD134)在许多情况下是有效的T细胞介导的免疫、控制T细胞的增殖和遇到特定抗原后的生存所必需的。我们先前发现，OX40的功能靶点是调节增殖的Survivin和极光B，以及调节生存的Bcl2抗凋亡家族成员。然而，OX40介导这些效应的细胞内途径尚不清楚。在这项研究中，我们证明了OX40信号可以靶向外周抗原反应的CD4T细胞中的典型的核因子-kappa B(nf-kappa B1)通路。在OX40缺乏的T细胞中，I-kappa Bα的磷酸化、核因子-kappa B1/p50和relA的核转位以及核因子-kappa B1的活性均受到损害。逆转录病毒转导活性的I-kappa B激酶，结构性地激活核因子-kappa-B1，挽救了OX40缺陷的T细胞的不良增殖和存活，这与Survivin、极光B和Bcl-2家族成员的表达和活性增加直接相关。此外，仅表达激活的licB激酶就足以恢复体内OX40缺陷T细胞对抗原的反应时的缺陷扩张和存活。因此，OX40信号通过控制细胞内增殖和存活靶点的表达和活性的核因子-kappa B1途径来调节T细胞的数量和活性。
The costimulatory molecule OX40 (CD134) is required in many instances for effective T cell-mediated immunity, controlling proliferation, and survival of T cells after encountering specific Ag. We previously found that the functional targets of OX40 are survivin and aurora B that regulate proliferation and Bcl-2 antiapoptotic family members that regulate survival. However, the intracellular pathways from OX40 that mediate these effects are unclear. In this study, we show that OX40 signaling can target the canonical NF-kappa B (NF-kappa B1) pathway in peripheral Ag-responding CD4 T cells. Phosphorylation of I kappa B alpha, nuclear translocation of NF-kappa B1/p50 and RelA, and NF-kappa B1 activity, are impaired in OX40-deficient T cells. Retroviral transduction of active I kappa B kinase that constitutively activates NF-kappa B1 rescues the poor expansion and survival of OX40-deficient T cells, directly correlating with increased expression and activity of survivin, aurora B, and Bcl-2 family members. Moreover, active licB kinase expression alone is sufficient to restore the defective expansion and survival of OX40-deficient T cells in vivo when responding to Ag. Thus, OX40 signals regulate T cell number and viability through the NF-kappa B1 pathway that controls expression and activity of intracellular targets for proliferation and survival.