Wakem P, Burns R P, Ramirez F, Zlotnick D, Ferbel B, Haidaris C G, Gaspari A A
Department of Dermatology, University of Rochester Medical Center, NY 14642, USA.
J Invest Dermatol. 2000 Jun;114(6):1085-92. doi: 10.1046/j.1523-1747.2000.00997.x.
The human CD80 costimulatory molecule is an important signal between professional antigen-presenting cells and T helper cells. The immunobiology of CD80 expression by keratinocytes, especially during allergic and irritant contact dermatitis, however, is less well understood. CD80 cell surface expression and gene transcription by keratinocytes was increased when keratinocytes were exposed to certain allergens (chemicals that induce inflammation via hapten-specific T cells) and irritants (chemicals that are toxic to epidermal cells). Therefore, the human CD80 promoter was cloned and luciferase reporter constructs containing various promoter fragments were engineered. Promoter mapping of these CD80 constructs in transiently transfected keratinocytes showed that a construct containing the proximal 231 bp immediately upstream of the transcription start site of the CD80 promoter was most active in keratinocytes and was inducible to a level ranging from 2- to 10-fold higher in keratinocytes treated with certain allergens and irritants, compared with untreated keratinocytes. This pattern of promoter fragment activity in keratinocytes is identical to that found in professional antigen-presenting cells. This is the first demonstration that the CD80 promoter is active in keratinocytes and that this activity is further increased in keratinocytes treated with certain allergens and irritants. These data suggest that allergens and irritants may, in part, break peripheral tolerance by their direct effects on keratinocyte costimulatory molecule expression, thereby facilitating interactions with epidermotropic T helper cells via the CD80-CD28 or CTLA-4 pathways.
人CD80共刺激分子是专职抗原呈递细胞与辅助性T细胞之间的重要信号。然而，角质形成细胞表达CD80的免疫生物学，尤其是在变应性和刺激性接触性皮炎期间，了解较少。当角质形成细胞暴露于某些变应原（通过半抗原特异性T细胞诱导炎症的化学物质）和刺激物（对表皮细胞有毒的化学物质）时，角质形成细胞的CD80细胞表面表达和基因转录增加。因此，克隆了人CD80启动子，并构建了含有各种启动子片段的荧光素酶报告基因构建体。在瞬时转染的角质形成细胞中对这些CD80构建体进行启动子定位分析表明，含有CD80启动子转录起始位点上游紧邻的231 bp片段的构建体在角质形成细胞中活性最高，与未处理的角质形成细胞相比，在用某些变应原和刺激物处理的角质形成细胞中，其诱导水平高出2至10倍。角质形成细胞中启动子片段的这种活性模式与专职抗原呈递细胞中的相同。这首次证明了CD80启动子在角质形成细胞中具有活性，并且在用某些变应原和刺激物处理的角质形成细胞中该活性进一步增强。这些数据表明，变应原和刺激物可能部分通过其对角质形成细胞共刺激分子表达的直接作用打破外周耐受，从而通过CD80 - CD28或CTLA - 4途径促进与亲表皮辅助性T细胞的相互作用。
