Single T Cell Sequencing Demonstrates the Functional Role alpha beta TCR Pairing in Cell Lineage and Antigen Specificity

Carter, J. A., Preall, J. B., Grigaityte, K., Goldfless, S. J., Jeffery, E., Briggs, A. W., Vigneault, F., Atwal, G. S. (July 2019) Single T Cell Sequencing Demonstrates the Functional Role alpha beta TCR Pairing in Cell Lineage and Antigen Specificity. Frontiers in Immunology, 10. Article Number:1516. ISSN 1664-3224

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Abstract

Although structural studies of individual T cell receptors (TCRs) have revealed important roles for both the alpha and beta chain in directing MHC and antigen recognition, repertoire-level immunogenomic analyses have historically examined the beta chain alone. To determine the amount of useful information about TCR repertoire function encoded within alpha beta 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 alpha and beta chains are only weakly associated with lineage, of pairings appear to synergistically drive TCR-MHC interactions. V alpha beta gene pairings were found to be the TCR feature most informative of T cell lineage, supporting the existence of germline-encoded paired alpha beta 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 alpha and beta chains that each recognize different known antigens, suggesting that alpha beta pairing is critical for the accurate inference of repertoire functionality. Together, these findings provide biological insight into the functional implications of alpha beta pairing and highlight the utility of single-cell sequencing in immunogenomics.

Item Type:	Paper
Subjects:	bioinformatics organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells bioinformatics > computational biology > algorithms organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > computational biology organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > immunity bioinformatics > computational biology > algorithms > machine learning organs, tissues, organelles, cell types and functions
CSHL Authors:	Atwal, Gurinder Singh Preall, Jonathan Carter, Jason A Grigaityte, Kristina
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Atwal lab CSHL labs > Preall lab School of Biological Sciences > Publications
Depositing User:	Matthew Dunn
Date:	31 July 2019
Date Deposited:	23 Aug 2019 21:00
Last Modified:	01 Feb 2024 20:53
PMCID:	PMC6684766
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38290

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