Williams I R, Ort R J, Kupper T S
Harvard Skin Diseases Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12780-4. doi: 10.1073/pnas.91.26.12780.
Resting epidermal keratinocytes do not express B7-1 and other known CD28 counterligands with costimulatory activity. The absence of these costimulators on keratinocytes correlates with their ability to preferentially induce T-cell anergy instead of T-cell activation. To test the hypothesis that keratinocytes expressing a CD28 counterligand would be more effective inducers of T-cell-mediated immune responses in skin, we prepared transgenic mice in which expression of the B7-1 costimulator was targeted to basal keratinocytes by using the human K14 promoter. Keratinocytes from the K14/B7-1 transgenic line expressed high levels of surface B7-1. No spontaneous inflammatory changes were seen in transgenic skin, but epicutaneous application of contact sensitizers to these mice elicited a stronger primary ear swelling response than in controls. Sites of initial hapten application in transgenic mice also responded much more strongly to reapplication of hapten to a remote cutaneous site. Epidermal cell suspensions from transgenic mice contained normal numbers of Langerhans cells and dendritic epidermal T cells when analyzed by flow cytometry. Systemic treatment of the transgenic mice with interferon gamma induced high levels of class II major histocompatibility complex expression on keratinocytes but was not sufficient to initiate an inflammatory response. We conclude that the constitutive expression of the B7-1 molecule in vivo on a nonprofessional antigen-presenting cell is not by itself sufficient to trigger inflammatory changes, but B7-1 expression amplifies the host immune responses after exposure to nonself antigens presented by B7-1-expressing cells.
静息状态的表皮角质形成细胞不表达B7-1及其他具有共刺激活性的已知CD28配体。角质形成细胞上缺乏这些共刺激分子与其优先诱导T细胞无能而非激活T细胞的能力相关。为了验证表达CD28配体的角质形成细胞在皮肤中能更有效地诱导T细胞介导的免疫反应这一假说，我们制备了转基因小鼠，其中通过使用人K14启动子将B7-1共刺激分子的表达靶向至基底角质形成细胞。来自K14/B7-1转基因系的角质形成细胞表达高水平的表面B7-1。在转基因皮肤中未观察到自发的炎症变化，但对这些小鼠经皮应用接触性致敏剂引发的初次耳部肿胀反应比对照组更强。在转基因小鼠中初次应用半抗原的部位，当再次将半抗原应用于远处皮肤部位时，反应也强烈得多。通过流式细胞术分析，转基因小鼠的表皮细胞悬液中朗格汉斯细胞和树突状表皮T细胞数量正常。用γ干扰素对转基因小鼠进行全身治疗可诱导角质形成细胞上高水平表达II类主要组织相容性复合体，但不足以引发炎症反应。我们得出结论，B7-1分子在体内非专职抗原呈递细胞上的组成性表达本身不足以引发炎症变化，但B7-1表达可在暴露于由表达B7-1的细胞呈递的非自身抗原后放大宿主免疫反应。
