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

胸腺是唯一能够支持淋巴细胞的两个主要亚群--传统T细胞和固有T细胞--发育的器官。然而，还没有人提出直接的机制(S)来解释他们不同发展背后的教条。一种未经测试的可能性规定，T细胞受体(TCR)信号强度的差异是采用常规与先天命运的主要决定因素。支持这一假说的例子依赖于这样的观察，即先天的而不是传统的CD8 T细胞表达几个激活标记，这些标记的表达与其胸腺内发育过程中感受到的信号强度成比例。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(CTECs)表面主要组织相容性I(MHCI)-多肽复合体的亲和力。这些复合体的产生依赖于cTECs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(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的多肽，因此产生不稳定的MHCI-多肽复合体，从而提供较弱的TCR刺激。相反，免疫蛋白酶体依赖的MHCI-肽复合体更稳定，因此具有诱导更强的TCR信号的能力。有趣的是，胸腺蛋白酶体缺陷小鼠(尽管在cTECs中表达免疫蛋白酶体)缺乏传统的CD8T细胞，但外周记忆/先天类CD8T细胞的比例显著增加。基于这些观察，我们假设固有的CD8胸腺细胞是由免疫蛋白酶体依赖的多肽选择的，而不是传统的CD8胸腺细胞，后者优先依赖于胸腺蛋白酶体产生的多肽。

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.