INHIBITION OF T CELLS BY A TUMOR ASSOCIATED PROTEIN

描述：（改编自申请人摘要）肿瘤逃避免疫

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.