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

CD 8+细胞毒性T淋巴细胞（CTL）识别的抗原结构 是通过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）蛋白 肽，通常长度为8-9个氨基酸。 大约一千 不同的肽-MHC-I复合物可能存在于任何特定的 MHC I类蛋白以足够的密度在细胞表面上， 与CD 8 + T细胞的有效相互作用。 为了了解这些 肽是从大量不同的 可通过蛋白水解片段化潜在产生的肽 在一个典型细胞产生的5000 - 10000种不同蛋白质中， 参与表征天然存在的肽， 由与MHC-I蛋白相关的CD 8 + CTL识别。 使用 CTL识别来自MHC不同个体的正常细胞的系统 (i.e.特异性应答同种异体细胞的同种异体反应性CTL）， 我们最近成功地描述了两种自然发生的 由同种异体反应性CTL克隆（2C）识别的肽， 与MHC-I蛋白Ld. 较小的肽，八聚体， 与Ld形成稳定的复合物，Ld是较大的肽（16个氨基酸， 长度）包括八聚体的整个序列，并且可能是其 产生这些肽的细胞中的前体 因为我们还 确定了这些肽的来源（“亲本蛋白质”），我们在 一个独特的系统来探索导致 特异性肽-MHC-I复合物的形成。 因为该 亲本蛋白是一种普遍存在的脱氢酶，其丰度可以是 通过一个简单的测定，我们还将探讨如何产生的 这些肽，它们对MHC I蛋白的亲和力，以及这些肽的结合， 相应的肽-MHC-I复合物对T细胞受体的影响 选择胸腺细胞，因为他们在胸腺成熟，这一过程是 最终负责成熟T细胞识别 并对多种外来肽--MHC-I产生特异性反应 复合物，而不是自身肽-MHC-I复合物（“自身耐受性”）。

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").