Unique and shared molecular features of human B and T lymphocyte memory differentiation

Abstract

Abstract Long-term immunity against infections and effective response to vaccination are dependent on remarkable and unique feature of lymphocytes referred as “memory generation”. Despite having multiple mice studies focused on naïve to memory transition of lymphocytes our understanding of human naïve and memory properties is limited. In this study we explored epigenetics (DNA methylation and accessible chromatin), transcriptomics and activation induced gene expression of FACS sorted naïve and memory subsets of B, CD4 T and CD8 T lymphocytes of healthy donors from GESTALT cohort. Shared and specific methylomes between B and T lymphocyte subsets were identified. The relationship between DNA methylation, chromatin accessibility and transcriptome through ATAC-Seq and RNA-Seq data from the same donors is established. Through in-silico analyses and by utilizing data from Roadmap Epigenomics project and ChromHMM, we further identified differentiation-specific connections between DNA methylation, chromatin accessibility, and histone modifications. Transcription factor motif analyses identifies presence of ARNT, OCT and NF-κB motifs around sites hypomethylated in B memory while ETS motifs are in memory-associated hyper-methylated sites. Interestingly, OCT motifs were also significantly enriched in B memory specific accessible chromatin. To understand the extent to which these epigenetic changes effected lymphocytes, we activated naïve and memory subsets of B and CD4+ T lymphocytes in vitro and assayed early and late gene expression changes. These findings will provide the foundation for future studies related to dysregulation of memory cell differentiation in aging and infections. Supported by Intramural Research Program of the National Institute on Aging.