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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=662871
• 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.

胸腺是能够支持两种主要淋巴细胞亚群（称为常规 T 细胞和先天 T 细胞）发育的唯一器官。然而，还没有提出直接的机制来解释它们不同发展背后的教条。一种未经检验的可能性规定，T 细胞受体 (TCR) 信号强度的差异是采用传统命运与先天命运的主要决定因素。支持这一假设的例子依赖于这样的观察：先天的而非传统的 CD8 T 细胞表达几种激活标记，这些标记的表达与其胸腺内发育过程中感知到的信号强度成正比。事实上，TCR 信号强度取决于细胞表面密度和对皮质胸腺上皮细胞 (cTEC) 表面主要组织相容性 I(MHCI)-肽复合物的亲和力。这些复合物的生成依赖于 cTEC 蛋白酶体机制，该机制主要由胸腺蛋白酶体和一小部分免疫蛋白酶体（蛋白酶体的两种不同形式）组成。由于胸腺蛋白酶体产生低亲和力肽，因此产生不稳定的 MHCI-肽复合物，从而提供较弱的 TCR 刺激。相比之下，免疫蛋白酶体依赖性 MHCI-肽复合物更稳定，因此具有引发更强 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 细胞的比例显着增加。基于这些观察，我们假设先天性 CD8 胸腺细胞是由免疫蛋白酶体依赖性肽选择的，这与传统 CD8 胸腺细胞不同，后者优先依赖于通过胸腺蛋白酶体产生的肽。