Precursors of human CD4(+) cytotoxic T lymphocytes identified by single-cell transcriptome analysis.
Precursors of human CD4(+) cytotoxic T lymphocytes identified by single-cell transcriptome analysis.
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DOI：
10.1126/sciimmunol.aan8664
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发表时间：
2018-01-19
影响因子：
24.8
通讯作者：
Vijayanand P
中科院分区：
文献类型：
--
作者：
Patil VS;Madrigal A;Schmiedel BJ;Clarke J;O'Rourke P;de Silva AD;Harris E;Peters B;Seumois G;Weiskopf D;Sette A;Vijayanand P
据报道，CD 4+细胞毒性T淋巴细胞（CD 4-CTL）在几种病毒感染中起保护作用。然而，很少有人知道，在人类的生物学CD 4-CTL的产生，其功能特性，和异质性，特别是在其他良好的描述CD 4+记忆T细胞亚群。我们在9000多个细胞中进行了单细胞RNA测序，以揭示人类CD 4-CTL的异质性、转录谱和克隆性。单细胞差异基因表达分析揭示了一系列已知的转录本，包括与细胞毒性和共刺激功能相关的几种转录本，这些转录本在TEMRA（表达CD 45 RA的效应记忆T细胞）亚群中以更高的水平表达，与中央记忆（TCM）和效应记忆（TEM）亚群中的CD 4 + T细胞相比，TEMRA亚群高度富集CD 4-CTL。在单细胞和大量亚群中的同时T细胞抗原受体（TCR）分析揭示，与TCM和TEM细胞相比，CD 4-TEMRA细胞显示出显著的克隆扩增，并且在先前感染登革病毒（DENV）的供体中，大多数CD 4-TEMRA是登革病毒（DENV）特异性的。CD 4-TEMRA的分布在供体之间是高度异质性的，通过单细胞分析鉴定出四个不同的簇。我们在TEMRA亚群中鉴定了CD 4-CTL效应细胞和前体细胞的不同簇;前体细胞与CD 4-CTL效应细胞共享TCR克隆型，并通过高表达白细胞介素-7受体来区分。我们对CD 4-CTL前体群体的鉴定可能有助于进一步研究CD 4-CTL如何在人体中产生，因此，可以深入了解可用于产生持久有效的CD 4-CTL免疫的机制。
CD4+ cytotoxic T lymphocytes (CD4-CTLs) have been reported to play a protective role in several viral infections. However, little is known in humans about the biology of CD4-CTL generation, their functional properties, and heterogeneity, especially in relation to other well-described CD4+ memory T cell subsets. We performed single-cell RNA sequencing in more than 9000 cells to unravel CD4-CTL heterogeneity, transcriptional profile, and clonality in humans. Single-cell differential gene expression analysis revealed a spectrum of known transcripts, including several linked to cytotoxic and costimulatory function that are expressed at higher levels in the TEMRA (effector memory T cells expressing CD45RA) subset, which is highly enriched for CD4-CTLs, compared with CD4+ T cells in the central memory (TCM) and effector memory (TEM) subsets. Simultaneous T cell antigen receptor (TCR) analysis in single cells and bulk subsets revealed that CD4-TEMRA cells show marked clonal expansion compared with TCM and TEM cells and that most of CD4-TEMRA were dengue virus (DENV)–specific in donors with previous DENV infection. The profile of CD4-TEMRA was highly heterogeneous across donors, with four distinct clusters identified by the single-cell analysis. We identified distinct clusters of CD4-CTL effector and precursor cells in the TEMRA subset; the precursor cells shared TCR clonotypes with CD4-CTL effectors and were distinguished by high expression of the interleukin-7 receptor. Our identification of a CD4-CTL precursor population may allow further investigation of how CD4-CTLs arise in humans and, thus, could provide insights into the mechanisms that may be used to generate durable and effective CD4-CTL immunity.
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影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
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Restifo NP
影响因子：
14.5
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Siffrin, Volker
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通讯作者：
Craig, Susan W.
影响因子：
30.5
作者：
Intlekofer, AM;Takemoto, N;Reiner, SL
通讯作者：
Reiner, SL
影响因子：
8.8
作者：
Hidalgo, L. G.;Einecke, G.;Halloran, P. F.
通讯作者：
Halloran, P. F.