ANALYSIS OF THE T CELL REPERTOIRE

T 细胞库分析

• 批准号: 3796544
• 负责人: R J HODES
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3796544
• 关键词: T cell receptor; T lymphocyte; athymic mouse; gene expression; laboratory mouse; laboratory rat; leukocyte activation /transformation; major histocompatibility complex; messenger RNA

When T cell receptor (TCR) expression was analyzed by flow cytometry and by mRNA quantitation, strain-specific decreases were detected in expression of 12 of the 22 known mouse Vbeta products, representing negative selection of potentially self-reactive T cells in mice expressing the corresponding self ligands. These deleting ligands also functioned as "superantigens" capable of stimulating T cells expressing the corresponding Vbeta products. Genetic mapping in all cases identified endogenous mouse mammary tumor (MMTV) proviruses encoding the Vbeta-specific deleting ligands. These Vbeta deletions fail to occur in athymic nude mice, demonstrating that the thymus is critical in tolerance by negative selection. Exogenous viruses were analyzed for their influences on T cell repertoire. Milk-borne MMTV induced Vbeta-14 deletion only in strains of mice bearing natural or transgenic I-E class II major histocompatibility complex (MHC) product. A murine leukemia virus which causes a mouse acquired immune deficiency syndrome (MAIDS) induced superantigen-like T cell activation in vitro. In vivo, this virus selectively activated and expanded CD4+ T cells expressing Vbeta-5, followed later in the course of infection by widespread immune deficiency in all T cells. Although Vbeta-specific superantigen effects are a model for the study of TCR selection, selection may more commonly depend on receptor specificity determined by multiple TCR alpha and beta chain components. Analysis of the expression of specific TCR Valpha/Vbeta pairs has indicated that Valpha/Vbeta pairing is non-random and that strain-specific differences exist in patterns of Valpha/Vbeta expression, providing a new approach to the study of repertoire selection. T cell responses to endogenous superantigen were also shown to be influenced by Valpha as well as Vbeta TCR expression. When TCR expression was analyzed in xenogeneic bone marrow transplantation between mouse and rat, it was found that tolerance to xenograft was accompanied by Vbeta-specific T cell deletions. In the class I-restricted response of mouse CD8+ T cells to HIV peptides, unique cross-reactive specificity patterns were accompanied by highly preferential use of specific Vbeta products.

当通过流式细胞术分析 T 细胞受体 (TCR) 表达并 通过 mRNA 定量，检测到菌株特异性降低 22 种已知小鼠 Vbeta 产物中 12 种的表达，代表 小鼠潜在自身反应性 T 细胞的阴性选择 表达相应的自身配体。 这些删除配体还 作为能够刺激T细胞表达的“超级抗原” 相应的Vbeta产品。 所有情况下的基因图谱 鉴定出内源性小鼠乳腺肿瘤（MMTV）原病毒，编码 Vbeta 特异性删除配体。 这些 Vbeta 缺失未能发生在 无胸腺裸鼠，证明胸腺对于耐受性至关重要 通过负选择。 分析外源病毒对 T 细胞的影响 剧目。 乳源性 MMTV 仅在以下菌株中诱导 Vbeta-14 缺失 具有天然或转基因 I-E II 类主要组织相容性的小鼠 复合体（MHC）产物。 一种引起小鼠白血病的鼠类白血病病毒 获得性免疫缺陷综合征 (MAIDS) 诱导的超抗原样 T 体外细胞活化。 在体内，该病毒选择性激活并 扩增表达 Vbeta-5 的 CD4+ T 细胞，随后在 所有 T 细胞中广泛的免疫缺陷导致感染。 尽管 Vbeta 特异性超抗原效应是研究 TCR 选择，选择可能更常见地取决于受体特异性 由多个 TCR α 和 β 链成分决定。 分析 特定 TCR Valpha/Vbeta 对的表达表明 Valpha/Vbeta 配对是非随机的，并且菌株特异性差异 存在于 Valpha/Vbeta 表达模式中，提供了一种新方法 曲目选择的研究。 T细胞对内源性的反应 超抗原也被证明受到 Valpha 和 Vbeta 的影响 TCR 表达。 当分析异种骨髓中的 TCR 表达时 小鼠和大鼠移植后发现，对 异种移植伴随着 Vbeta 特异性 T 细胞缺失。 在 小鼠 CD8+ T 细胞对 HIV 肽的 I 类限制性反应，独特 交叉反应特异性模式伴随着高度 优先使用特定Vbeta产品。