Single T Cell Sequencing Demonstrates the Functional Role of αβ TCR Pairing in Cell Lineage and Antigen Specificity
Single T Cell Sequencing Demonstrates the Functional Role of αβ TCR Pairing in Cell Lineage and Antigen Specificity
复制标题
单 T 细胞测序证明 αβ TCR 配对在细胞谱系和抗原特异性中的功能作用
作者：
Jason A. Carter;Jonathan Preall;Kristina Grigaityte;Stephen J. Goldfless;E. Jeffery;Adrian W. Briggs;Francois Vigneault;G. Atwal
尽管单个T细胞受体（TCR）的结构研究已经揭示了α和β链在指导MHC和抗原识别中的重要作用，但库水平的免疫基因组学分析历史上只检查了β链。为了确定αβ配对中编码的TCR库功能的有用信息量，我们分析了使用两种不同的高通量单细胞测序方法捕获的近100，000个独特的CD 4+和CD 8 + T细胞的配对TCR序列。我们的研究结果表明，在健康的CD 4+和CD 8+库中几乎没有重叠，共享的TCR序列具有显著更短的CDR 3序列，对应于更高的生成概率。我们进一步利用信息论和机器学习的工具表明，虽然α和β链与谱系仅弱相关，但αβ配对似乎协同驱动TCR-MHC相互作用。发现Vαβ基因配对是最能提供T细胞谱系信息的TCR特征，支持种系编码的配对αβ TCR-MHC相互作用基序的存在。最后，使用具有已知抗原特异性的序列数据库注释我们的TCR对，我们证明大约三分之一的T细胞具有各自识别不同已知抗原的α和β链，这表明αβ配对对于准确推断库功能至关重要。总之，这些发现提供了对αβ配对的功能意义的生物学见解，并强调了单细胞测序在免疫基因组学中的实用性。
Although structural studies of individual T cell receptors (TCRs) have revealed important roles for both the α and β chain in directing MHC and antigen recognition, repertoire-level immunogenomic analyses have historically examined the β chain alone. To determine the amount of useful information about TCR repertoire function encoded within αβ pairings, we analyzed paired TCR sequences from nearly 100,000 unique CD4+ and CD8+ T cells captured using two different high-throughput, single-cell sequencing approaches. Our results demonstrate little overlap in the healthy CD4+ and CD8+ repertoires, with shared TCR sequences possessing significantly shorter CDR3 sequences corresponding to higher generation probabilities. We further utilized tools from information theory and machine learning to show that while α and β chains are only weakly associated with lineage, αβ pairings appear to synergistically drive TCR-MHC interactions. Vαβ gene pairings were found to be the TCR feature most informative of T cell lineage, supporting the existence of germline-encoded paired αβ TCR-MHC interaction motifs. Finally, annotating our TCR pairs using a database of sequences with known antigen specificities, we demonstrate that approximately a third of the T cells possess α and β chains that each recognize different known antigens, suggesting that αβ pairing is critical for the accurate inference of repertoire functionality. Together, these findings provide biological insight into the functional implications of αβ pairing and highlight the utility of single-cell sequencing in immunogenomics.
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通讯作者：
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Yin L;Huseby E;Scott-Browne J;Rubtsova K;Pinilla C;Crawford F;Marrack P;Dai S;Kappler JW
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Kappler JW
影响因子：
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通讯作者：
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作者：
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