Distinct T Cell Receptor (TCR) gene segment usage and MHC-restriction between foetal and adult thymus
Distinct T Cell Receptor (TCR) gene segment usage and MHC-restriction between foetal and adult thymus
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胎儿和成人胸腺之间不同的 T 细胞受体 (TCR) 基因片段使用和 MHC 限制
DOI：
10.1101/2023.09.20.558574
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Rowell J
中科院分区：
文献类型：
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作者：
Rowell J
本研究测定了来自胎儿和年轻成年小鼠的CD 4 + CD 8+双阳性（DP）、CD 4 + CD 8-单阳性（SP 4）和CD 4-CD 8+（SP 8）胸腺细胞群中重排的TCRβ和TCRα链序列。我们发现，生命阶段比细胞类型对TCRβ和TCRα基因片段的使用有更大的影响。在所有人群中，胎儿组均偏向于3 'TRAV和5' TRAJ重排，而成人组使用更多的5 'TRAV基因片段，表明胎儿DP细胞中进行性TCRα重排发生频率较低。当我们通过氢化可的松处理使年轻成人DP胸腺细胞分化同步时，新恢复的DP胸腺细胞群体显示出更多的胎儿样3 'TRAV和5' TRAJ基因片段使用。在胎儿中，我们鉴定了与成人相比，MHC限制对SP中α链和β链组合TCR J使用和CDR 1xCDR 2（V区）使用的影响较小，表明MHC限制对胎儿TCR库的影响较弱。胎儿TCRβ库的多样性较低，分布较不均匀，非模板插入较少，所有胎儿群体比成人包含更多的克隆型扩增。胎儿和成人胸腺TCR库之间的差异与胎儿胸腺产生的αβ T细胞具有与成人T细胞不同的特性和功能一致：它们的库较少受MHC限制的控制，偏好特定基因片段的使用，多样性较少，具有更多的克隆型扩增，并且更接近于由基因组序列编码。
Here, we sequenced rearranged TCRβ and TCRα chain sequences in CD4+ CD8+ double positive (DP), CD4+ CD8-single positive (SP4) and CD4-CD8+(SP8) thymocyte populations from the foetus and young adult mouse. We found that life-stage had a greater impact on TCRβ and TCRα gene segment usage than cell-type. Foetal repertoires showed bias towards 3’TRAV and 5’TRAJ rearrangements in all populations, whereas adult repertoires used more 5’TRAV gene segments, suggesting that progressive TCRα rearrangements occur less frequently in foetal DP cells. When we synchronised young adult DP thymocyte differentiation by hydrocortisone treatment the new recovering DP thymocyte population showed more foetal-like 3’TRAV and 5’TRAJ gene segment usage. In foetus we identified less influence of MHC-restriction on α-chain and β-chain combinatorial VxJ usage and CDR1xCDR2 (V region) usage in SP compared to adult, indicating weaker impact of MHC-restriction on the foetal TCR repertoire. The foetal TCRβ repertoire was less diverse, less evenly distributed, with fewer non-template insertions, and all foetal populations contained more clonotypic expansions than adult. The differences between the foetal and adult thymus TCR repertoires are consistent with the foetal thymus producing αβT-cells with properties and functions that are distinct from adult T-cells: their repertoire is less governed by MHC-restriction, with preference for particular gene segment usage, less diverse with more clonotypic expansions, and more closely encoded by genomic sequence.