Essential role of NF-κB-inducing kinase in T cell activation through the TCR/CD3 pathway
Essential role of NF-κB-inducing kinase in T cell activation through the TCR/CD3 pathway
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DOI：
10.4049/jimmunol.169.3.1151
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发表时间：
2002-08-01
影响因子：
4.4
通讯作者：
Mitani, T
中科院分区：
文献类型：
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作者：
Matsumoto, M;Yamada, T;Mitani, T
核因子-kappaB诱导激酶(NIK)通过淋巴毒素-β受体信号转导参与小鼠淋巴样器官发生。为了阐明Nik在通过TCR/CD3和共刺激途径激活T细胞中的作用，我们研究了带有Nik突变株的Aly小鼠T细胞的功能。NIK突变型T细胞在抗CD3刺激下表现出增殖和IL-2的分泌受损，这些效应是由成熟和未成熟T细胞中的NF-kappaB活性受损引起的，成熟T细胞中的NF-kappaB活性受损也与激活的NF-kappaB的维持失败有关。相比之下，对共刺激信号的反应在Aly小鼠中大部分保留，这表明Nik并不是唯一耦合到共刺激信号的。用蛋白激酶C(PKC)抑制剂刺激Nik突变的T细胞时，增殖反应比对照组更严重，提示Nik和PKC以协同方式控制T细胞的激活。我们还证明了NIK和PKC参与了TCR/CD3下游不同的NF-kappaB激活途径。这些结果表明，Nik在设定T细胞激活阈值方面发挥了关键作用，并在一定程度上解释了Aly小鼠免疫缺陷的原因。
NF-kappaB-inducing kinase (NIK) is involved in lymphoid organogenesis in mice through lymphotoxin-beta receptor signaling. To clarify the roles of NIK in T cell activation through TCR/CD3 and costimulation pathways, we have studied the function of T cells from aly mice, a strain with mutant NIK. NIK mutant T cells showed impaired proliferation and IL-2 production in response to anti-CD3 stimulation, and these effects were caused by impaired NF-kappaB activity in both mature and immature T cells; the impaired NF-kappaB activity in mature T cells was also associated with the failure of maintenance of activated NF-kappaB. In contrast, responses to costimulatory signals were largely retained in aly mice, suggesting that NIK is not uniquely coupled to the costimulatory pathways. When NIK mutant T cells were stimulated in the presence of a protein kinase C (PKC) inhibitor, proliferative responses were abrogated more severely than in control mice, suggesting that both NIK and PKC control T cell activation in a cooperative manner. We also demonstrated that NIK and PKC are involved in distinct NF-kappaB activation pathways downstream of TCR/CD3. These results suggest critical roles for NIK in setting the threshold for T cell activation, and partly account for the immunodeficiency in aly mice.