NON-H-2 HISTOCOMPATIBILITY GENES AND ENCODED ANTIGENS

组织相容性（H）抗原由定位在外部的基因编码 的主要组织相容性复合体组成了强大的 组织移植成功的障碍。 虽然家庭 非H-2H抗原在小鼠中的表达是重要的 用于研究T细胞应答调节的模型系统， 几乎不知道这些的起源和功能 抗原 这一持续的计划旨在阐明 对多种和单一H抗原的反应机制。 我们最近发现H抗原是由 逆转录病毒和肿瘤病毒的种系整合。 的 拟议的研究计划是一个多方面的方法， 了解T细胞的机制和调节 对H抗原的反应和这种反应的成员的鉴定 重要的家庭。 第一批实验旨在揭示 这是体外T细胞对 免疫显性抗原及其与T细胞反应的相关性 vivo. （1）优先呈现显性基因的潜在作用 抗原的H-2K/D分子，（2）亲和力的差异， T细胞上的IL-2受体的数量对显性和 优势抗原，和（2）不同类别的优势抗原 将研究辅助性和细胞溶解性T细胞。 t细胞 将分析对单个H抗原的应答，以确定（1） H-2K分子的离散区域在H抗原中的作用 表达和确定Ir基因状态，（2）影响 H抗原特异性T细胞使用的T细胞受体V基因在 抗原特异性和H-2限制性，和（3）关系 体内和体外T细胞应答机制之间的联系。 这些研究将得到克隆和 非H-2H基因的鉴定。 观察到SV40 T抗原在转基因小鼠中被视为H抗原， 通过确定不同启动子的影响来扩展， 侧翼区作为H抗原表达。 的 一种新的乳腺肿瘤病毒与突变型H 将通过克隆该逆转录病毒来确认抗原，以评估其 编码H抗原的能力 大衣与 颜色和H基因突变将扩展，以确认大衣， 颜色突变回复导致H抗原的丢失。 最后， 逆转录病毒载体将用作插入诱变剂， 克隆单个H基因; 逆转录病毒将有助于首次克隆H基因， 粘粒文库。

Histocompatibility (H) antigens encoded by genes mapping outside of the major histocompatibility complex comprise a formidable barrier to successful tissue transplantation. Although the family of non-H-2 H antigens in the mouse has served as an important model system for studying the regulation of the T cell response, virtually nothing is known of the origins and functions of these antigens. This continuing program has been aimed at elucidating the mechanisms of responses to multiple and single H antigens. We have recently discovered that H antigens are generated by germline integration of retroviruses and tumor viruses. The proposed research plan is a multi-faceted approach to understanding the mechanisms and regulation of the T cell response to H antigens and the identification of members of this important family. The first experiments are aimed at revealing the basis for the preferential, in vitro T cell response to immunodominant antigens and its relevance to T cell responses in vivo. Potential roles for (1) preferential presentation of dominant antigens by H-2K/D molecules, (2) differences in affinity and number of IL-2 receptors on T cells specific for dominant and dominated antigens, and (2) different classes of dominant antigens for helper and cytolytic T cells will be investigated. The T cell response to single H antigens will be analyzed to determine (1) the role of discrete regions of H-2K molecules in H antigen presentation and determination of Ir gene status, (2) the effects of T cell receptor V genes used by H antigen-specific T cells on antigen specificity and H-2 restriction, and (3) the relationship between the mechanisms of in vivo and in vitro T cell responses. These studies will be complemented by the cloning and identification of non-H-2 H genes. The observation that the SV40 T-antigen is seen as an H antigen in transgenic mice will be extended by determining the effects of different promoters and flanking regions on its expression as an H antigen. The association between a new mammary tumor virus and a mutant H antigen will be confirmed by cloning this retrovirus to assess its ability to encode this H antigen. The relationship between coat color and H gene mutations will be extended to confirm that coat color mutant reversions lead to the loss of H antigens. Finally, retroviral vectors will be employed as insertional mutagens to inactivate a single H gene; the cloning of the integrated retrovirus will facilitate the first cloning of an H gene from a cosmid library.