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Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection. [Display omitted] • scATAC-seq and scRNA-seq reveal expansion of an MBC subset in chronic LCMV infection • A distinct chronic MBC subset is associated with increased IFN-I-associated ISG signature • The chromatin landscape of MBCs is established during a critical window early in infection • IFN-I dynamics govern memory B cell epigenome and phenotype in chronic viral infection Chronic viral infection disrupts the ability to form long-lived B cell-mediated protective immunity, but the mechanisms are unclear. Cooper et al. demonstrate a key role of type I interferon (IFN-I) in governing memory B cell identity and show that the chromatin landscape and phenotype of memory B cells are set during a critical early window of IFN-I exposure. [ABSTRACT FROM AUTHOR]

Immune imprinting describes how the first exposure to a virus shapes immunological outcomes of subsequent exposures to antigenically related strains. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron breakthrough infections and bivalent COVID-19 vaccination primarily recall cross-reactive memory B cells induced by prior Wuhan-Hu-1 spike mRNA vaccination rather than priming Omicron-specific naive B cells. These findings indicate that immune imprinting occurs after repeated Wuhan-Hu-1 spike exposures, but whether it can be overcome remains unclear. To understand the persistence of immune imprinting, we investigated memory and plasma antibody responses after administration of the updated XBB.1.5 COVID-19 mRNA vaccine booster. We showed that the XBB.1.5 booster elicited neutralizing antibody responses against current variants that were dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 spike. Therefore, immune imprinting persists after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 booster vaccination, which will need to be considered to guide future vaccination. [Display omitted] • XBB.1.5 COVID-19 mRNA vaccine elicits neutralizing antibodies against current variants • Depletion of Wuhan-Hu-1 S-reactive plasma antibodies abrogate XBB.1.5 neutralization • XBB.1.5 COVID-19 mRNA vaccine primary recalls Wuhan-Hu-1 S-reactive memory B cells Immune imprinting occurs after repeated Wuhan-Hu-1 spike exposures, but it is unclear whether it can be overcome. Tortorici et al. show that the updated XBB.1.5 mRNA COVID-19 booster elicits neutralizing antibodies and memory B cells against variants that are dominated by recall of pre-existing memory B cells induced by Wuhan-Hu-1 spike exposure. Immune imprinting thus persists post XBB.1.5 booster vaccination. [ABSTRACT FROM AUTHOR]

Germinal center (GC)-derived memory B cells (MBCs) are critical for humoral immunity as they differentiate into protective antibody-secreting cells during re-infection. GC formation and cellular interactions within the GC have been studied in detail, yet the exact signals that allow for the selection and exit of MBCs are not understood. Here, we showed that IL-4 cytokine signaling in GC B cells directly downregulated the transcription factor BCL6 via negative autoregulation to release cells from the GC program and to promote MBC formation. This selection event required additional survival cues and could therefore result in either GC exit or death. We demonstrate that both increasing IL-4 bioavailability or limiting IL-4 signaling disrupted MBC selection stringency. In this way, IL-4 control of BCL6 expression serves as a tunable switch within the GC to tightly regulate MBC selection and affinity maturation. [Display omitted] • IL-4 promotes BCL6 to a point of negative autoregulation in GC B cells • IL-4-mediated loss of BCL6 promotes memory differentiation but not survival • BCL6 modulation via IL-4 signaling can regulate memory B cell selection B cells undergo rounds of selection and affinity maturation within germinal centers (GCs) to differentiate into long-lasting, protective memory cells. Shehata et al. study the role of IL-4 in the GC and determine that its regulation of the transcription factor BCL6 releases cells from the GC program and allows entry into the memory B cell program. [ABSTRACT FROM AUTHOR]