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

CD8细胞毒性T淋巴细胞(CTL)识别的抗原结构 细胞表面复合体是由I类的非共价缔合形成的吗？ 短链主要组织相容性复合体(MHC)的蛋白质 多肽，通常长度为8-9个氨基酸。大约一千人左右 不同的多肽-MHC-I复合体可能存在于任何特定的 MHC-I类蛋白在细胞表面的密度足以 与CD8 T细胞的有效相互作用。为了了解这些 多肽是从数量巨大的不同的 可能由蛋白水解性碎裂产生的多肽 在一个典型细胞产生的5,000-10,000种不同蛋白质中，我们是 致力于表征自然产生的多肽，这些多肽 与MHC-I蛋白相关的CD8 CTL识别。使用 CTL识别不同MHC个体正常细胞的系统 (即对同种异体细胞有特异性反应的同种异体CTL)， 我们最近成功地描述了两个自然发生的 由同种异体反应CTL克隆(2C)识别的多肽 与MHC-I蛋白LD相关。较小的多肽，一个八聚体， 与LD形成稳定的络合物，较大的多肽(16个氨基酸在 长度)包括八聚体的整个序列，并且可能是其 产生这些多肽的细胞中的前体。因为我们还 确定了这些多肽的来源(“母体蛋白”) 汉德独一无二的系统，用于探索导致 形成特异性多肽-MHC-I复合体。鉴于 亲本蛋白是一种普遍存在的脱氢酶，其丰度可以 通过一个简单的测试来衡量，我们还将探索如何产生 这些肽，它们与MHC I蛋白的亲和力，以及与MHC I蛋白的结合 与T细胞受体对应的多肽-MHC-I复合体影响 胸腺细胞在胸腺中成熟时的选择，这是一个 最终导致成熟T细胞的识别能力 并对种类繁多的外源多肽-MHC-I作出特异性反应 但不能与自体多肽-MHC-I复合物结合(“自我耐受”)。

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").