Thymoproteasomes produce unique peptide motifs for positive selection of CD8(+) T cells.
Thymoproteasomes produce unique peptide motifs for positive selection of CD8(+) T cells.
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DOI：
10.1038/ncomms8484
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发表时间：
2015-06-23
影响因子：
16.6
通讯作者：
Murata S
中科院分区：
文献类型：
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作者：
Sasaki K;Takada K;Ohte Y;Kondo H;Sorimachi H;Tanaka K;Takahama Y;Murata S
胸腺中的阳性选择提供了低亲和力的T细胞受体(TCR)结合，以支持潜在有用的自我主要组织相容性复合体I类(MHC-I)限制性T细胞的发展。CD8+T细胞的最佳阳性选择需要表达β5T胸腺蛋白酶体(TCP)的胸腺皮质上皮细胞。然而，TCP如何管理积极选择尚不清楚。在这里，我们展示了TCP在消化的多肽和MHC-I相关多肽中产生独特的切割基序。有趣的是，携带这些TCP依赖基序的MHC-I相关多肽富含低亲和力的TCR配体，在抗原特异性TCR转基因模型中有效地诱导具有功能活性的CD8+T细胞的阳性选择。这些结果表明，TCPs通过优先产生低亲和力的TCR配体多肽，有助于CD8+T细胞的阳性选择。蛋白酶体将细胞内的蛋白质消化成多肽，然后作为抗原呈递给淋巴细胞。在这里，作者表明，胸腺上皮特异性蛋白酶体亚基以一种有利于模型蛋白与T细胞受体弱结合的模式切割模型蛋白，从而促进T细胞的阳性选择。
Positive selection in the thymus provides low-affinity T-cell receptor (TCR) engagement to support the development of potentially useful self-major histocompatibility complex class I (MHC-I)-restricted T cells. Optimal positive selection of CD8+ T cells requires cortical thymic epithelial cells that express β5t-containing thymoproteasomes (tCPs). However, how tCPs govern positive selection is unclear. Here we show that the tCPs produce unique cleavage motifs in digested peptides and in MHC-I-associated peptides. Interestingly, MHC-I-associated peptides carrying these tCP-dependent motifs are enriched with low-affinity TCR ligands that efficiently induce the positive selection of functionally competent CD8+ T cells in antigen-specific TCR-transgenic models. These results suggest that tCPs contribute to the positive selection of CD8+ T cells by preferentially producing low-affinity TCR ligand peptides. Proteasomes digest intracellular proteins into peptides that are then presented to lymphocytes as antigens. Here the authors show that a thymic epithelium-specific proteasome subunit cuts model proteins in a pattern favouring their weak binding to T cell receptor, and thus T cell positive selection.