CD5-CK2 binding/activation-deficient mice are resistant to experimental autoimmune encephalomyelitis: Protection is associated with diminished populations of IL-17-expressing T cells in the central nervous system
CD5-CK2 binding/activation-deficient mice are resistant to experimental autoimmune encephalomyelitis: Protection is associated with diminished populations of IL-17-expressing T cells in the central nervous system
复制标题
DOI：
10.4049/jimmunol.177.12.8542
复制
发表时间：
2006-12-15
影响因子：
4.4
通讯作者：
Raman, Chander
中科院分区：
文献类型：
--
作者：
Axtell, Robert C.;Xu, Liang;Raman, Chander
调节致脑炎性T细胞的分化和持续存在对于实验性自身免疫性脑脊髓炎（EAE）的发展至关重要。我们最近报道，CD 5在T细胞中具有一种依赖于补体的促生存活性，在EAE的诱导和进展中发挥直接作用。我们预测，CD 5调节T细胞凋亡/生存通过激活CK 2，一个促生存丝氨酸/苏氨酸激酶，与受体。为了验证这一假设，我们产生了表达CD 5但不能结合和激活CK 2的小鼠，并评估了它们对EAE的易感性。我们发现CD 5-CK 2信号通路缺陷的小鼠对EAE的发展具有抵抗性。对EAE的抵抗与共表达IFN-γ和IL-17的效应浸润Th细胞群体的急剧减少有关，并且在较小程度上与引流淋巴结和脊髓中表达IFN-γ或IL-17的细胞的显著减少有关。我们进一步表明，缺乏CD 5-CK 2信号转导的T细胞在初次刺激后过度增殖;然而，在再刺激后，它们迅速发展为无反应性，并表现出升高的活化诱导的细胞死亡。我们的研究结果提供了CD 5-CK 2通路在T细胞活化和效应T细胞在神经炎性疾病中的持久性中的直接作用。这项研究预测，靶向IFN-γ（+）/IL-17（+）浸润Th细胞将有助于治疗多发性硬化症和其他系统性自身免疫性疾病。
Regulating the differentiation and persistence of encephalitogenic T cells is critical for the development of experimental autoimmune encephalomyelitis (EAE). We reported recently that CD5 has an engagement-dependent prosurvival activity in T cells that played a direct role in the induction and progression EAE. We predicted that CD5 regulates T cell apoptosis/survival through the activation of CK2, a prosurvival serine/threonine kinase that associates with the receptor. To test this hypothesis, we generated mice expressing CD5 with the inability to bind and activate CK2 and assessed their susceptibility to EAE. We found mice deficient in CD5-CK2 signaling pathway were mostly resistant to the development of EAE. Resistance to EAE was associated with a dramatic decrease in a population of effector infiltrating Th cells that coexpress IFN-gamma and IL-17 and, to a lesser extent, cells that express IFN-gamma or IL-17 in draining lymph nodes and spinal cords. We further show that T cells deficient in CD5-CK2 signaling hyperproliferate following primary stimulation; however, following restimulation, they rapidly develop nonresponsiveness and exhibit elevated activation-induced cell death. Our results provide a direct role for CD5-CK2 pathway in T cell activation and persistence of effector T cells in neuroinflammatory disease. This study predicts that targeting of IFN-gamma(+)/IL-17(+) infiltrating Th cells will be useful for the treatment of multiple sclerosis and other systemic autoimmune diseases.