Kajiura Fumiko, Sun Shijie, Nomura Takashi, Izumi Keisuke, Ueno Tomoo, Bando Yoshimi, Kuroda Noriyuki, Han Hongwei, Li Yi, Matsushima Akemi, Takahama Yousuke, Sakaguchi Shimon, Mitani Tasuku, Matsumoto Mitsuru
Department of Molecular and Environmental Pathology, School of Medicine, University of Tokushima, Tokushima, Japan.
J Immunol. 2004 Feb 15;172(4):2067-75. doi: 10.4049/jimmunol.172.4.2067.
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.
胸腺细胞与胸腺基质之间的物理接触对于T细胞成熟至关重要，并塑造了外周的T细胞库。控制这些过程的基质成分仍然难以捉摸。我们使用一种具有突变型核因子κB诱导激酶（NIK）的小鼠品系来研究自身耐受破坏的潜在机制。这种NIK突变品系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。通过移植来自NIK突变小鼠的胚胎胸腺，在无胸腺裸鼠中重现了NIK突变小鼠中出现的自身免疫性疾病，并且通过供应外源性免疫调节性T细胞得以挽救。缺乏正常NIK的胸腺基质导致免疫调节性T细胞产生受损，这与外周组织限制性抗原的表达改变有关，表明NIK在胸腺微环境中建立中枢耐受方面起着至关重要的作用。
