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（称为常规T细胞和先天性T细胞）发育的器官。然而，没有提出直接的机制来解释其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。支持这一假设的实例依赖于观察到先天性而非常规CD 8 T细胞表达几种活化标志物，其表达与其胸腺内发育期间感知的信号强度成比例。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（cTEC）表面上呈递的主要组织相容性I（MHCI）-肽复合物的亲和力。这些复合物的产生依赖于cTECs蛋白酶体机制，其主要由胸腺蛋白酶体和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，因此递送较弱的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）缺乏常规的CD 8 T细胞，但外周记忆/先天性CD 8样T细胞的比例显著增加。基于这些观察结果，我们假设先天性CD 8胸腺细胞选择的免疫蛋白酶体依赖性肽在合同的常规CD 8胸腺细胞，它优先依赖于通过胸腺蛋白酶体产生的肽。

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.