ANTIGEN PRESENTATION AND COSTIMULATION BY KERATINOCYTES

描述：炎症部位的角质形成细胞表达II类主要 组织相容性复合物（MHC）分子对IFN-γ的应答。 II类MHC的表达允许角质形成细胞展示肽-MHCII 复合物并作为CD 4 T细胞的抗原呈递细胞（APC）发挥功能。 以前的研究表明，II类阳性角质形成细胞是 致耐受性APC，但角质形成细胞抗原呈递的影响， Th 1和Th 2 T细胞亚群的活化尚未得到解决。 的 待检验的中心假设是II类抗原呈递 阳性上皮细胞对Th 1和Th 2细胞具有不同的作用 亚群，Th 1细胞发展为无反应性，Th 2细胞通过 产生进一步抑制Th 1的细胞因子（即IL-4和IL-10 功能 II类抗原阳性T细胞的抗原呈递 角质形成细胞也可以受到来自B7的共刺激分子的影响， 家族，并且已经提出（但未使用体内模型证明）， B7-1和B7-2对CD 4 T细胞的分化具有相反的作用。 为了进一步了解角质形成细胞表达II类MHC和 共刺激分子影响完整皮肤中T细胞免疫的诱导， 具体目标如下：（1）确定Th 1和Th 2 对皮肤抗原的反应由抗原呈递调节， 组成型表达II类MHC的转基因表皮角质形成细胞 抗原 小鼠基底膜MHC Ⅱ类分子的组成性表达 角质形成细胞将通过表达编码以下两者的转基因来实现 人K14控制下的小鼠II类MHC分子的链 启动子 半抗原特异性T细胞免疫的发展 将通过比较接触来分析表皮致敏性 超敏反应（CHS）应答、T细胞细胞因子合成和抗半抗原 转基因小鼠和对照中的抗体产生。 (2)以确定是否 单独的II类阳性角质形成细胞（在不存在II类阳性角质形成细胞的情况下， 朗格汉斯细胞和树突状细胞）可以启动CD 4 T细胞应答， 皮肤抗原 允许组成型表达类 通过角质形成细胞的II类MHC将繁殖到II类无效小鼠上，具体地说， 在角质形成细胞上重建II类表达，但没有其他皮肤 装甲运兵车 (3)为了确定CD 28反配体（B7-1 vs. B7-2 vs. B7-3）影响Th 1或Th 2的相对活化， CHS应答期间的Th 2 T细胞。 在这些过程中产生的动物模型 研究将是唯一强大的定义分子机制， 表达II类MHC的上皮APC促进口服耐受， 其他形式的外周耐受性。

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.