Targeted reconstruction of T cell receptor sequence from single cell RNA-seq links CDR3 length to T cell differentiation state

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...

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Bibliographic Details
Published in:Nucleic acids research 2017-09, Vol.45 (16), p.e148-e148
Main Authors: Afik, Shaked, Yates, Kathleen B, Bi, Kevin, Darko, Samuel, Godec, Jernej, Gerdemann, Ulrike, Swadling, Leo, Douek, Daniel C, Klenerman, Paul, Barnes, Eleanor J, Sharpe, Arlene H, Haining, W Nicholas, Yosef, Nir
Format: Article
Language:English
Subjects:
Algorithms
Animals
CD8-Positive T-Lymphocytes - cytology
CD8-Positive T-Lymphocytes - immunology
Cell Differentiation
Complementarity Determining Regions - chemistry
Female
Gene Expression Profiling
Humans
Male
Methods Online
Mice, Inbred C57BL
Middle Aged
Receptors, Antigen, T-Cell - chemistry
Receptors, Antigen, T-Cell - metabolism
Sequence Analysis, RNA - methods
Single-Cell Analysis
Software
Yellow fever virus - immunology
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkx615