NFκB-inducing kinase deficiency results in the development of a subset of regulatory T cells, which shows a hyperproliferative activity upon glucocorticoid-induced TNF receptor family-related gene stimulation
NFκB-inducing kinase deficiency results in the development of a subset of regulatory T cells, which shows a hyperproliferative activity upon glucocorticoid-induced TNF receptor family-related gene stimulation
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DOI：
10.4049/jimmunol.175.3.1651
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发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Noelle, RJ
中科院分区：
文献类型：
--
作者：
Lu, LF;Gondek, DC;Noelle, RJ
CD 4（+）CD 25（+）调节性T细胞（T-reg）在维持免疫耐受中起重要作用。糖皮质激素诱导的TNFR家族相关基因（GITR）在T-reg上优先高水平表达，已被证明是调节T-reg介导的抑制的关键参与者。最近的一项研究报道，胸腺基质中NF-κ B诱导激酶（NIK）的表达对T-reg的正常产生很重要，但对其抑制能力不重要。在这份报告中，我们已经表明，T-reg从NIK缺陷小鼠显示过度增殖活动后，GITR刺激通过IL-2的非依赖性机制。此外，高剂量IL-2，抗CD 28刺激，或GITR配体转导的骨髓来源的树突细胞用作APC另外的实验已经显示，NIK缺陷型小鼠具有更高的CD 4（+）CD 25（+）CD 62 L（低）T-细胞比率，而NIK缺陷型小鼠具有更高的CD 4（+）CD 25（+）CD 62 L（低）T-细胞比率。reg在胸腺和外周中的表达均高于其野生型同窝仔。该CD 62（低）亚群负责GITR刺激后的过度增殖活性。这些数据表明NIK在控制CD 4（+）CD 25（+）调节性T细胞的发育和扩增中具有新的作用。
CD4(+)CD25(+) regulatory T cells (T-reg) play an important role in maintaining immunologic tolerance. Glucocorticoid-induced TNFR family-related gene (GITR) expressed preferentially at high levels on T-reg has been shown to be a key player of regulating T-reg-mediated suppression. A recent study reports that NF-kappa B-inducing kinase (NIK) expression in thymic stroma is important for the normal production of T-reg but not for its suppression capacity. In this report, we have shown that T-reg from NIK-deficient mice display hyperproliferative activities upon GITR stimulation through an IL-2-independent mechanism. Furthermore, high dose IL-2, anti-CD28 stimulation, or GITR ligand-transduced bone marrow-derived dendritic cells used as APC (culture conditions which drive T-reg proliferation in vitro) could not ablate this difference in proliferative activity between NIK-deficient and wild-type T-reg. Additional experiments have shown NIK-deficient mice have a higher ratio of CD4(+)CD25(+)CD62L(low) T-reg both in thymus and periphery than their wild-type littermates. This CD62(low) subset is responsible for the hyperproliferative activity upon GITR stimulation. These data suggest a novel role of NIK in controlling the development and expansion of CD4(+)CD25(+) regulatory T cells.