Epigenetic priming underpins enhanced memory B cell differentiation

Abstract

Abstract Immunological memory is a hallmark of the adaptive immune response. Memory B cells (MBC) have increased affinity, expression of costimulatory molecules, and capacity to proliferate and differentiate than their naïve counterparts; however, the epigenetic mechanisms that control enhanced MBC functions are currently unknown. Using a murine model of influenza infection, nucleoprotein (NP)-specific MBC and follicular naïve B cells (nB) were isolated and the chromatin accessibility and transcriptional landscape determined by ATAC and RNA-seq, respectively. MBC displayed distinct gene expression profiles from nB, including an upregulation of plasma cell (PC) signature genes and significant overall increases in total mRNA content. Furthermore, MBC display an open and primed chromatin conformation in gene regulatory regions that map to transcription factors controlling either PC (Prdm1 and Irf4), germinal center (Aicda), or MBC (Zbtb32) fates. These data reveal additional novel MBC-specific transcription factor networks and describe an epigenetic “antigen experience” signature that correlates with enhanced MBC function. To confirm the importance of these molecular changes, naïve and memory mice were challenged with a heterosubtypic influenza infection or isolated and cultured with CD40L, IL-4, and IL-5. In vivo, MBC form germinal centers earlier and to a higher frequency than nB. MBC also form significantly more NP+IgG+ PCs by flow cytometry and ELISPOT, corroborating the open chromatin signature. Ex vivo, MBCs upregulated primed transcription factors earlier than nB, validating the enhanced formation of CD138+ PCs. These data describe an epigenetic basis for enhanced the differentiation capacity and function of MBC.