INHIBITION OF T CELLS BY A TUMOR ASSOCIATED PROTEIN

描述：（改编自申请人的摘要）肿瘤逃避免疫 尽管肿瘤相关抗原频繁表达， 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CD 8 + T细胞的识别，很少有研究 解决了CD 4 + T细胞应答的肿瘤细胞逃避;然而，最佳 抗肿瘤免疫应答需要CD 8+和CD 4 + T细胞的参与 肿瘤相关抗原特异性细胞。在这里，我们展示了 上皮糖蛋白（mEGP），人类癌的小鼠同源物 相关抗原GA 733 -2，阻断抗原特异性MHC II类T细胞 由骨髓来源的树突状细胞诱导的活化。mEGP还阻止 在其同源肽存在下活化转基因T细胞， 蛋白抗原（例如，鸡蛋溶菌酶和卵清蛋白）。我们假设 阻断发生在树突状细胞抗原呈递水平 细胞，并通过干扰MIHC II类肽的组装而发生 复杂.这些结果反映了MIHC I类相关的下调， 抗原呈递，并证明了一种新的机制， 肿瘤相关抗原参与破坏抗肿瘤免疫 反应在本申请中，我们将首先确定mEGP函数 仅在抗原呈递细胞的水平上，并且对 T细胞（目标1）。然后我们将确定mEGP蛋白的哪些部分 是否需要其抑制作用，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 蛋白质GA 733在人T细胞系统中具有相似的活性（Aim 3）。人类 模型将用于探索mEGP和GA 733的作用是否是由于 组织蛋白酶活性的改变，已知其在II类中起作用 组装（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，这样做提供了一个框架， 了解它们在正常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.