ANTIGEN PRESENTATION AND COSTIMULATION BY KERATINOCYTES

描述：炎症部位的角质形成细胞主要表达II类。 组织相容性复合体(MHC)分子对干扰素-γ的反应。 第二类MHC的表达允许角质形成细胞展示多肽-MHC II 作为CD4T细胞的抗原提呈细胞(APC)。 以前的研究表明，II类阳性角质形成细胞是 耐受性APC，但角质形成细胞抗原提呈对 Th1和Th2 T细胞亚群的激活尚未得到解决。这个 需要检验的中心假设是第II类抗原呈递 阳性上皮细胞对Th1和Th2细胞有不同的作用 Th1细胞发生无能，Th2细胞通过 产生细胞因子(即IL-4和IL-10)，进一步抑制Th1 功能。第II类阳性的T细胞抗原提呈 角质形成细胞也可以受到B7共刺激分子的影响 而且已经提出(但没有用活体模型证明) B7-1和B7-2对CD4T细胞的分化具有相反的作用。 为进一步了解角质形成细胞如何表达II类MHC和 共刺激分子影响完整皮肤T细胞免疫的诱导， 提出以下具体目标：(1)确定Th1和Th2如何 对皮肤抗原的反应是由抗原提呈调节的 组成性表达II类MHC的转基因表皮角质形成细胞 抗原。第二类MHC在小鼠基底细胞中的组成性表达 角质形成细胞将通过表达编码这两种基因的基因来实现 人类K14基因调控下小鼠第II类MHC分子链 推动者。半抗原特异性T细胞免疫的研究进展 皮肤表面致敏作用将通过比较接触方式进行分析 超敏反应、T细胞细胞因子合成和抗半抗原 转基因小鼠和对照小鼠的抗体产生。(2)确定是否 单独的II类阳性角质形成细胞(在没有II类阳性的情况下 朗格汉斯细胞和树突状细胞)可以启动CD4T细胞对 皮肤抗原。允许类的结构性表达的转基因 角质形成细胞产生的II类MHC将被培育成II类缺失小鼠，特别是 在角质形成细胞上重建II类表达，但不能在其他皮肤上表达 APC。(3)测定CD28反配体(B7-1与B7-2与 角质形成细胞表达的B7-3)影响Th1或Th1的相对激活 Th2T细胞在CHS应答中的作用。在这些过程中产生的动物模型 研究将通过以下方式在定义分子机制方面独一无二地强大 哪些上皮APC表达II类MHC促进口服耐受和 其他形式的外围容忍。

DESCRIPTION: Keratinocytes at sites of inflammation express class II major histocompatibility complex (MHC) molecules in response to IFN-gamma. Expression of class II MHC allows keratinocytes to display peptide-MHC II complexes and function as antigen-presenting cells (APC) for CD4 T cells. Previous studies have indicated that class II positive keratinocytes are tolerogenic APC, but the effects of keratinocyte antigen presentation on activation of the Th1 and Th2 T cell subsets have not been addressed. The central hypothesis to be tested is that antigen presentation by class II positive epithelial cells has distinct effects on an TH1 and Th2 cell subsets, with Th1 cells developing anergy and Th2 cells responding by production of cytokines (i.e. IL-4 and IL-10) that further inhibit Th1 function. Antigen presentation to T cells by class II positive keratinocytes can also be influenced by costimulatory molecules from the B7 family, and it has been proposed (but not proven using in vivo models) that B7-1 and B7-2 have opposing effects on the differentiation of CD4 T cells. To further understand how keratinocyte expression of class II MHC and costimulatory molecules affects induction of T cell immunity in intact skin, the following specific aims are proposed: (1) to determine how Th1 and Th2 responses to cutaneous antigens are modulated by antigen presentation on transgenic epidermal keratinocytes constitutively expressing class II MHC antigens. Constitutive expression of class II MHC in murine basal keratinocytes will be achieved by expression of transgenes encoding both chains of a mouse class II MHC molecule under the control of the human K14 promoter. The development of hapten-specific T cell immunity after epicutaneous sensitization will be analyzed by comparing contact hypersensitivity (CHS) responses, T cell cytokine synthesis, and anti-hapten antibody production in transgenic mice and controls. (2) To determine if class II positive keratinocytes alone (in the absence of class II positive Langerhans cells and dendritic cells) can initiate CD4 T cell responses to cutaneous antigens. Transgenes permitting constitutive expression of class II MHC by keratinocytes will be bred onto class II null mice, specifically reconstituting class II expression on keratinocytes, but no other cutaneous APC. (3) To determine whether the CD28 counterligand (B7-1 vs. B7-2 vs. B7-3) expressed by keratinocytes influences relative activation of Th1 or Th2 T cells during CHS responses. The animal models generated during these studies will be uniquely powerful in defining the molecular mechanisms by which epithelial APC expressing class II MHC promote oral tolerance and other forms of peripheral tolerance.