NF-κB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner
NF-κB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner
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DOI：
10.4049/jimmunol.172.4.2067
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发表时间：
2004-02-15
影响因子：
4.4
通讯作者：
Matsumoto, M
中科院分区：
文献类型：
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作者：
Kajiura, F;Sun, S;Matsumoto, M
胸腺细胞和胸腺基质之间的物理接触对于T细胞成熟是必不可少的，并且塑造外周中的T细胞库。控制这些过程的基质成分仍然难以捉摸。我们使用具有突变的NF-κ B诱导激酶（NIK）的小鼠品系来检查自身耐受性破坏的潜在机制。这种NIK突变株表现出自身免疫性和胸腺结构紊乱，基质中Rel蛋白表达异常。在NIK突变小鼠中，控制自身反应性T细胞的免疫调节性T细胞的产生受损。在NIK突变小鼠中观察到的自身免疫性疾病通过移植来自NIK突变小鼠的胚胎胸腺而在无胸腺裸鼠中复制，并且这通过供应外源性免疫调节T细胞而被拯救。胸腺间质免疫调节T细胞的生产受损，没有正常的NIK与外周组织限制性抗原的表达改变，这表明在胸腺微环境中的NIK在建立中枢耐受性的重要作用。
Physical contact between thymocytes and the thymic stroma is essential for T cell maturation and shapes the T cell repertoire in the periphery. Stromal elements that control these processes still remain elusive. We used a mouse strain with mutant NF-kappaB inducing kinase (NIK) to examine the mechanisms underlying the breakdown of self-tolerance. This NIK-mutant strain manifests autoimmunity and disorganized thymic structure with abnormal expression of Rel proteins in the stroma. Production of immunoregulatory T cells that control autoreactive T cells was impaired in NIK-mutant mice. The autoimmune disease seen in NIK-mutant mice was reproduced in athymic nude mice by grafting embryonic thymus from NIK-mutant mice, and this was rescued by supply of exogenous immunoregulatory T cells. Impaired production of immunoregulatory T cells by thymic stroma without normal NIK was associated with altered expression of peripheral tissue-restricted Ags, suggesting an essential role of NIK in the thymic microenvironment in the establishment of central tolerance.