Abstract
Lymphoblastoid cell lines (LCLs) are generated by transforming primary B cells with Epstein-Barr virus (EBV) and are used extensively as model systems in viral oncology, immunology, and human genetics research. In this study, we characterized single-cell transcriptomic profiles of five LCLs and present a simple discrete-time simulation to explore the influence of stochasticity on LCL clonal evolution. Single-cell RNA sequencing (scRNA-seq) revealed substantial phenotypic heterogeneity within and across LCLs with respect to immunoglobulin isotype; virus-modulated host pathways involved in survival, activation, and differentiation; viral replication state; and oxidative stress. This heterogeneity is likely attributable to intrinsic variance in primary B cells and host-pathogen dynamics. Stochastic simulations demonstrate that initial primary cell heterogeneity, random sampling, time in culture, and even mild differences in phenotype-specific fitness can contribute substantially to dynamic diversity in populations of nominally clonal cells.
Highlights
Lymphoblastoid cell lines (LCLs) are immortalized cells prepared by in vitro transformation of resting primary B cells from peripheral blood with Epstein–Barr virus (EBV) (Bird et al, 1981; Anderson and Gusella, 1984)
We recently described a gene expression program having low expression of LMP1 and NFkB targets which was unique to early infection (Latency IIb) relative to an otherwise identical population of LCLs (Messinger et al, 2019)
Publicly available data sets were obtained for commercially available samples of the GM12878 and GM18502 LCLs, which were generated as previously reported by Osorio and colleagues (Osorio et al, 2019)
Summary
Lymphoblastoid cell lines (LCLs) are immortalized cells prepared by in vitro transformation of resting primary B cells from peripheral blood with Epstein–Barr virus (EBV) (Bird et al, 1981; Anderson and Gusella, 1984). LCLs are used extensively in research as a model for EBV-associated malignancies including diffuse large B cell lymphoma (Nichele et al, 2012; Tazzari et al, 1999) and post-transplant lymphoproliferative disorder (Markasz et al, 2009; Rea et al, 1994). Because EBV is a nonmutagenic transformant in this context, LCLs constitute an important renewable source of human cells and genomic DNA that are used in immunological, genetic, and virology research (Calıskan et al, 2014; Choy et al, 2008; Oh et al, 2013; Stark et al, 2010; Volkova et al, 2019).
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