Targeted reconstruction of T cell receptor sequence from single cell RNA-seq links CDR3 length to T cell differentiation state.
Targeted reconstruction of T cell receptor sequence from single cell RNA-seq links CDR3 length to T cell differentiation state.
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DOI：
10.1093/nar/gkx615
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发表时间：
2017-09-19
影响因子：
14.9
通讯作者：
Yosef N
中科院分区：
文献类型：
--
作者：
Afik S;Yates KB;Bi K;Darko S;Godec J;Gerdemann U;Swadling L;Douek DC;Klenerman P;Barnes EJ;Sharpe AH;Haining WN;Yosef N
T 细胞区室必须包含 T 细胞受体 (TCR) 库和细胞状态的多样性，以提供针对病原体的有效免疫力。然而，目前尚不清楚 TCR 的差异如何导致 T 细胞状态的异质性。单细胞 RNA 测序 (scRNA-seq) 可以同时测量单细胞的 TCR 序列和全局转录谱。然而，目前从 scRNA-seq 推断 TCR 的方法的灵敏度有限，并且需要较长的测序读数，从而增加了成本并减少了可进行可行分析的细胞数量。在这里，我们介绍 TRAPeS，这是一种公开可用的工具，可以有效地从短读 scRNA-seq 库中提取 TCR 序列信息。我们应用它来研究人类和小鼠 CD8+ T 细胞反应的异质性，并表明它比现有方法更准确、更灵敏。将 TRAPeS 与对黄热病病毒 (YFV) 单个表位特异的 CD8+ T 细胞的转录组分析相结合，我们发现最近描述的“幼稚样”记忆群体比效应记忆表型细胞具有明显更长的 CDR3 区域，并且与种系序列的差异更大。这表明 TCR 的使用与 CD8+ T 细胞对 YFV 反应的分化状态相关。
The T cell compartment must contain diversity in both T cell receptor (TCR) repertoire and cell state to provide effective immunity against pathogens. However, it remains unclear how differences in the TCR contribute to heterogeneity in T cell state. Single cell RNA-sequencing (scRNA-seq) can allow simultaneous measurement of TCR sequence and global transcriptional profile from single cells. However, current methods for TCR inference from scRNA-seq are limited in their sensitivity and require long sequencing reads, thus increasing the cost and decreasing the number of cells that can be feasibly analyzed. Here we present TRAPeS, a publicly available tool that can efficiently extract TCR sequence information from short-read scRNA-seq libraries. We apply it to investigate heterogeneity in the CD8+ T cell response in humans and mice, and show that it is accurate and more sensitive than existing approaches. Coupling TRAPeS with transcriptome analysis of CD8+ T cells specific for a single epitope from Yellow Fever Virus (YFV), we show that the recently described ‘naive-like’ memory population have significantly longer CDR3 regions and greater divergence from germline sequence than do effector-memory phenotype cells. This suggests that TCR usage is associated with the differentiation state of the CD8+ T cell response to YFV.
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