PEPTIDE/MHC-I COMPLEXES AND CD8+ T-CELLS

肽/MHC-I 复合物和 CD8 T 细胞

• 批准号: 2101440
• 负责人: HERMAN N EISEN
• 金额: $ 25.21万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-07 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2101440
• 关键词: CD8 molecule; MHC class I antigen; T cell receptor; antibody; chemical binding; cytotoxic T lymphocyte; genetically modified animals; histocompatibility; immune tolerance /unresponsiveness; laboratory mouse; laboratory rabbit; peptide analog; peptides; protein biosynthesis; proteolysis; synthetic peptide; tissue /cell culture

The antigenic structures recognized by CD8+ cytotoxic T lymphocytes (CTL) are cell surface complexes formed by noncovalent association of class I proteins of the major histocompatibility complex (MHC) with short peptides, typically 8-9 amino acids in length. Around a thousand different peptide-MHC-I complexes are likely to exist for any particular MHC class I protein on a cell's surface at a sufficient density for effective interaction with CD8+ T cells. To understand how these peptides are selected from the enormously greater number of different peptides that can be potentially generated by proteolytic fragmentation of the 5,000-10,000 different proteins produced by a typical cell, we are engaged in characterizing the naturally occurring peptides that are recognized by CD8+ CTL in association with MHC-I proteins. Using a system in which CTL recognize normal cells from MHC-different individuals (i.e. alloreactive CTL that specifically respond to allogeneic cells), we have recently succeeded in characterizing two naturally occurring peptides that are recognized by an alloreactive CTL clone (2C) in association with the MHC-I protein Ld. The smaller peptide, an octamer, forms stable complexes with Ld, the larger peptide (16 amino acids in length) includes the entire sequence of the octamer and is probably its precursor in the cells that produce these peptides. since we have also identified the source ("parent protein") of these peptides we have in hand a unique system for exploring the biochemical pathways that lead to the formation of specific peptide-MHC-I complexes. Inasmuch as the parent protein is a ubiquitous dehydrogenase whose abundance can be measured by a simple assay, we will also explore how the generation of these peptides, their affinity for MHC I proteins, and the binding of the corresponding peptide-MHC-I complexes to T cell receptors influence the selection of thymocytes as they mature in the thymus, a process that is ultimately responsible for the capacity of mature T cells to recognize and respond specifically to an enormous variety of foreign peptide-MHC-I complexes but not to self-peptide-MHC-I complexes ("self-tolerance").

CD8+细胞毒性T淋巴细胞（CTL）识别的抗原结构 是由 I 类非共价缔合形成的细胞表面复合物 主要组织相容性复合体 (MHC) 的蛋白质，具有短 肽，通常长度为 8-9 个氨基酸。 一千左右 任何特定的肽-MHC-I 复合物都可能存在 MHC I 类蛋白以足够的密度存在于细胞表面 与 CD8+ T 细胞有效相互作用。 要了解这些如何 肽是从大量不同的肽中选出的 可能通过蛋白水解断裂产生的肽 在典型细胞产生的 5,000-10,000 种不同蛋白质中，我们 致力于表征天然存在的肽 被 CD8+ CTL 与 MHC-I 蛋白结合识别。 使用 CTL 识别来自 MHC 不同个体的正常细胞的系统 （即对同种异体细胞特异性反应的同种异体反应性 CTL）， 我们最近成功地表征了两种自然发生的 被同种异体反应性 CTL 克隆 (2C) 识别的肽 与 MHC-I 蛋白 Ld 的关联。 较小的肽，八聚体， 与 Ld 形成稳定的复合物，Ld 是较大的肽（其中 16 个氨基酸） 长度）包括八聚体的整个序列，并且可能是它的 产生这些肽的细胞中的前体。 因为我们也有 确定了我们所拥有的这些肽的来源（“母体蛋白质”） 手一个独特的系统来探索导致的生化途径 特定肽-MHC-I 复合物的形成。 由于 亲本蛋白是一种普遍存在的脱氢酶，其丰度可以是 通过简单的测定进行测量，我们还将探索如何生成 这些肽、它们对 MHC I 蛋白的亲和力以及 T 细胞受体相应的肽-MHC-I 复合物影响 当胸腺细胞在胸腺中成熟时对其进行选择，这一过程是 最终负责成熟 T 细胞的识别能力 并对多种外源肽-MHC-I 产生特异性反应 复合物，但不与自肽-MHC-I 复合物（“自我耐受”）。