INHIBITION OF T CELLS BY A TUMOR ASSOCIATED PROTEIN

描述：(改编自申请者的摘要)肿瘤逃避免疫 尽管肿瘤相关抗原经常表达，但监测 可以被T细胞识别。虽然已经描述了许多机制 为了解释肿瘤细胞逃避CD8 T细胞的识别，很少有研究 解决了肿瘤细胞逃避CD4T细胞反应的问题；然而，最佳方案 抗肿瘤免疫反应需要CD8和CD4T的共同参与 肿瘤相关抗原的特异性细胞。在这里，我们向您展示这只老鼠 上皮糖蛋白(MEGP)，人类癌症的小鼠同源物 相关抗原GA733-2阻断抗原特异性MHC II类T细胞 骨髓来源的树突状细胞诱导的活化。MEGP还会阻止 转基因T细胞在其同源多肽和 蛋白质抗原(例如，鸡蛋溶菌酶和卵清蛋白)。我们假设 这种阻断发生在树突状细胞提呈抗原的水平上。 细胞，并通过干扰MIHC类Il肽的组装而发生 很复杂。这些结果反映了MIHC I类相关基因的下调 许多肿瘤的抗原提呈，并展示了一种新的机制，通过这种机制 肿瘤相关抗原参与破坏抗肿瘤免疫 回应。在本应用程序中，我们将首先建立mEGP函数 仅在抗原提呈细胞水平上，并不直接影响 T细胞(目标1)。然后我们将确定mEGP蛋白的哪些部分 是其抑制作用所必需的，以及这种作用是否发生在 内体水平(目标2)。最后，我们将确定人类是否 蛋白GA733在人类T细胞系统中具有类似的活性(目标3)。人类 模型将被用来探索mEGP和GA733的影响是否由于 已知在II类中起作用的组织蛋白酶活性的改变 装配(目标3)。总体目标是通过以下方式确定分子途径 这些蛋白质的功能，并在这样做时提供了一个框架 了解它们在正常细胞和肿瘤细胞中的生物学功能。

DESCRIPTION: (Adapted from applicant's abstract) Tumors evade immune surveillance despite the frequent expression of tumor-associated antigens that can be recognized by T cells. While a number of mechanisms have been described to explain tumor cell escape from recognition by CD8+ T cells, few studies have addressed tumor cell evasion of CD4+ T cell responses; nevertheless, optimal anti-tumor immune responses require the participation of both CD8+ and CD4+ T cells specific for tumor-associated antigens. Here, we show that mouse epithelial glycoprotein (mEGP), the mouse homologue of a human carcinoma associated antigen GA733-2, blocks antigen-specific MHC class II T cell activation induced by bone marrow derived dendritic cells. mEGP also blocks activation of transgenic T cells in the presence of their cognate peptide and protein antigens (e.g., hen egg lysozyme and ovalbumin). We hypothesize that the blockade occurs at the level of antigen presentation by the dendritic cells, and occurs by interfering with the assembly of MIHC class Il peptide complex. These results mirror the down-regulation of MIHC class I-associated antigen presentation in many tumors, and demonstrate a novel mechanism by which a tumor-associated antigen participates in subverting an anti-tumor immune response. In this application we will first establish that mEGP functions solely at the level of the antigen presenting cell and has no direct effect on the T cell (Aim 1). Then we will determine which portions of the mEGP protein are needed for its inhibitory effect and whether this effect occurs at the level of the endosome (Aim 2). Finally, we will determine whether the human protein GA733 has similar activity in a human T cell system (Aim 3). The human model will be used to explore whether the effects of mEGP and GA733 are due to alteration of cathepsin activity which is known to play a role in class II assembly (Aim 3). The overall objective is to identify the molecular pathway by which these proteins function and in doing so provide a framework for understanding their biologic functions in normal and neoplastic cells.