Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7-1 antigen.
Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7-1 antigen.
复制标题
表皮角质形成细胞组成型表达 B7-1 抗原的转基因小鼠出现过度且持续的皮肤迟发型超敏反应。
DOI：
10.1172/jci117411
复制
发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Gaspari,AA
中科院分区：
文献类型：
--
作者：
Nasir,A;Ferbel,B;Salminen,W;Barth,RK;Gaspari,AA
由于小鼠角质形成细胞是用于T细胞活化的致耐受性抗原呈递细胞，因此在转基因小鼠体内将第二信号分子如B7-1的表达靶向表皮角质形成细胞（KC）。用于产生转基因小鼠的表达载体由角蛋白14启动子组成，该启动子与编码小鼠B7-1的cDNA的全长开放阅读框5'融合（每个基因组10至30个转基因拷贝）。通过用CTLA-4/IG融合蛋白原位免疫染色尾部皮肤的冷冻切片来评估B7-1细胞表面蛋白的表达，揭示了转基因小鼠的所有表皮KC的B7细胞表面表达的高水平，并且在非转基因动物中缺乏这种表达。这种转基因小鼠（来自三种不同的创始小鼠）的皮肤在大体上和组织学上是正常的，具有正常数量的朗格汉斯细胞和树突状表皮T细胞。免疫挑战的转基因小鼠与表皮半抗原，如异硫氰酸荧光素显示增强和持久的迟发型超敏反应，与非转基因对照相比，具有改变的动力学分辨率。这些数据表明，在正常的非转基因小鼠中，KC的致耐受性抗原呈递通过与专业APC竞争迁移到表皮的抗原特异性T淋巴细胞中的TCR占用，在抑制T细胞介导的皮肤炎症中起重要的生理作用。这也意味着表皮细胞对B7-1基因表达的调节改变可能是一些慢性皮肤病中皮肤“高反应性”的原因。
Since mouse keratinocytes are tolerogenic antigen presenting cells for T cell activation, the expression of second signal molecules such as B7-1 was targeted to epidermal keratinocytes (KC) in vivo in transgenic mice. The expression vector used to create transgenic mice consisted of a keratin 14 promoter fused 5' to the full length open reading frame of the cDNA encoding mouse B7-1 (between 10 and 30 copies of the transgene per genome). Expression of B7-1 cell surface protein was assessed by in situ immunostaining of cryostat sections of tail skin with CTLA-4/Ig fusion protein, revealing high levels of cell surface expression of B7 by all epidermal KC of transgenic mice, and a lack of such expression in nontransgenic animals. The skin of such transgenic mice (derived from three different founder mice) was grossly and histologically normal, with normal numbers of Langerhans cells and dendritic epidermal T cells. Immunologic challenge of transgenic mice with epicutaneous haptens such as fluorescein isothiocyanate revealed enhanced and persistent delayed-type hypersensitivity responses, with an altered kinetics of resolution when compared with nontransgenic controls. These data indicate that in normal, nontransgenic mice, tolerogenic antigen presentation by KC plays an important physiologic role in damping T cell-mediated inflammation in the skin by competing with professional APC for TCR occupancy in antigen specific T-lymphocytes that migrate into the epidermis. This also implies that altered regulation of B7-1 gene expression by epidermal cells may account for skin "hyperresponsiveness" encountered in some chronic dermatologic disorders.Images