Deciphering the Nature of The Peptide Repertoire Supporting Positive Selection of CD8 T cells

破译支持 CD8 T 细胞阳性选择的肽库的性质

• 批准号: RGPIN-2014-06101
• 负责人: Rafei, Moutih
• 金额: $ 2.55万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=567595
• 关键词: Deciphering; Nature; Peptide; Repertoire; Supporting

The thymus is the sole organ capable of supporting the development of two major subsets of lymphocytes known as conventional and innate T cells. However, no direct mechanism(s) has been proposed to explain the dogma behind their divergent development. One untested possibility stipulates differences in T-cell receptor (TCR) signal strength as a major determinant of adopting a conventional versus innate fate. Examples supporting this hypothesis rely on the observation that innate, but not conventional CD8 T cells, express several activation markers whose expression is proportional to the signal strength perceived during their intrathymic development. In fact, TCR signal strength depends on both cell surface density and affinity to major histocompatibility I(MHCI)-peptide complexes presented on the surface of cortical thymic epithelial cells (cTECs). The generation of these complexes relies on the cTECs proteasomal machinery, which is mainly composed of thymoproteasomes and a minor fraction of immunoproteasomes (two distinct forms of proteasomes). As the thymoproteasome generates low affinity peptides, unstable MHCI-peptide complexes are yielded delivering therefore weaker TCR stimulation. In contrast, immunoproteasome-dependent MHCI-peptide complexes are more stable and thus, endowed with the capacity of eliciting stronger TCR signals. Interestingly, thymoproteasome-deficient mice (although expressing immunoproteasomes in cTECs) lack conventional CD8 T cells but harbor a noticeable increase in the proportion of peripheral memory/innate-like CD8 T cells. Based on these observations, we hypothesize that innate CD8 thymocytes are selected by immunoproteasome-dependent peptides in contract to conventional CD8 thymocytes, which rely preferentially on peptides generated via the thymoproteasome.

胸腺是唯一能够支持常规T细胞和先天T细胞这两种主要淋巴细胞亚群发育的器官。然而，没有直接的机制被提出来解释它们不同发展背后的教条。一种未经测试的可能性是，t细胞受体（TCR）信号强度的差异是采用传统和先天命运的主要决定因素。支持这一假设的例子依赖于对先天CD8 T细胞的观察，而不是传统的CD8 T细胞，表达几种激活标记物，其表达与胸腺内发育过程中感知的信号强度成正比。事实上，TCR信号强度取决于细胞表面密度和对胸腺皮质上皮细胞（cTECs）表面的主要组织相容性I（MHCI）肽复合物的亲和力。这些复合物的产生依赖于ctec蛋白酶体机制，其主要由胸腺蛋白酶体和一小部分免疫蛋白酶体（两种不同形式的蛋白酶体）组成。由于胸腺蛋白酶体产生低亲和力肽，产生不稳定的mhci肽复合物，因此提供较弱的TCR刺激。相比之下，依赖免疫蛋白酶体的mhci肽复合物更稳定，因此具有激发更强的TCR信号的能力。有趣的是，胸腺蛋白酶体缺陷小鼠（尽管在ctec中表达免疫蛋白酶体）缺乏传统的CD8 T细胞，但外周记忆/先天样CD8 T细胞的比例明显增加。基于这些观察结果，我们假设先天CD8胸腺细胞是由免疫蛋白酶体依赖肽选择的，而传统CD8胸腺细胞则优先依赖由胸腺蛋白酶体产生的肽。