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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]

Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection. Here, we investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs preferentially differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation temporally coincided with transient interferon (IFN)-γ production by Tfh cells. Depletion of IFN-γ in Tfh cells prevented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-γ was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted differentiation of a CXCR3+ GC B cell subset that were precursors of lung-BRMs and CXCR3+ memory B cells in the mediastinal lymph node. Absence of IFN-γ signaling or T-bet in GC B cells prevented CXCR3+ pre-memory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses. Thus, Tfh-cell-derived IFN-γ is critical for lung-BRM development and pulmonary immunity, with implications for vaccination strategies targeting BRMs. [Display omitted] • B6. Bcl6 fl/fl Cd4 cre/+ mice lack lung-resident memory B cells (BRMs) • Lung-BRMs fail to differentiate in bone marrow chimeras in which Tfh cells are Ifng −/− • IfngR1 −/− , Tbx21 −/− , and Stat1 − / − B cells fail to differentiate into lung-BRMs • T-bet expression in GC B cells is required for the development of lung-BRM precursors Lung-resident memory B cells (lung-BRMs) provide superior protection against respiratory viruses. Arroyo-Díaz et al. examine the requirements for lung-BRM development and reveal that IFN-γ production by Tfh cells is essential for the differentiation of memory B cell precursors that give rise to lung-BRMs and subsequent protection against heterosubtypic influenza infection. [ABSTRACT FROM AUTHOR]

How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after SARS-CoV-2 Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of the COVID-19 mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reactions, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with a marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies. ▪ • SARS-CoV-2 BA.1 breakthrough infection recalls cross-reactive RBD memory B cells (MBCs) • Recruitment of BA.1-restricted naive B cells to ASC and MBC-repertoires is limited • Longitudinal tracking reveals repertoire evolution up to 6 months post infection • Late remodeling is associated with improved MBC affinity and neutralization breadth How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains unclear. Sokal et al. show that SARS-CoV-2 Omicron BA.1 breakthrough infections induce late remodeling and maturation of the pre-existing memory B cell pool, with progressively improved MBC affinity and neutralization breadth but limited recruitment of BA.1-restricted naive B cells. [ABSTRACT FROM AUTHOR]

Seasonal influenza vaccination elicits hemagglutinin (HA)-specific memory B (Bmem) cells, and although multiple Bmem cell populations have been characterized, considerable heterogeneity exists. We found that HA-specific human Bmem cells differed in the expression of surface marker FcRL5 and transcriptional factor T-bet. FcRL5+T-bet+ Bmem cells were transcriptionally similar to effector-like memory cells, while T-betnegFcRL5neg Bmem cells exhibited stem-like central memory properties. FcRL5+ Bmem cells did not express plasma-cell-commitment factors but did express transcriptional, epigenetic, metabolic, and functional programs that poised these cells for antibody production. Accordingly, HA+ T-bet+ Bmem cells at day 7 post-vaccination expressed intracellular immunoglobulin, and tonsil-derived FcRL5+ Bmem cells differentiated more rapidly into antibody-secreting cells (ASCs) in vitro. The T-bet+ Bmem cell response positively correlated with long-lived humoral immunity, and clonotypes from T-bet+ Bmem cells were represented in the secondary ASC response to repeat vaccination, suggesting that this effector-like population predicts influenza vaccine durability and recall potential. [Display omitted] • FcRL5+T-bet+ memory B cells are molecularly programmed for effector function • FcRL5+ T-bet+ memory B cells are metabolically poised to form antibody-secreting cells • FcRL5+ T-bet+ memory B cells predict long-lived antibody responses to flu vaccination Seasonal influenza vaccination recalls pre-existing memory B cells for immune protection. Here, Nellore et al. show that intramuscular influenza vaccination elicits a population of effector memory B cells that are transcriptionally, epigenetically, and metabolically poised for antibody production. The magnitude of this FcRL5- and T-bet-expressing effector memory subset response correlates with long-lived antibody responses to influenza vaccination. [ABSTRACT FROM AUTHOR]

Memory B cells (MBCs) can persist for a lifetime, but the mechanisms that allow their long-term survival remain poorly understood. Here, we isolated and analyzed human splenic smallpox/vaccinia protein B5-specific MBCs in individuals who were vaccinated more than 40 years ago. Only a handful of clones persisted over such an extended period, and they displayed limited intra-clonal diversity with signs of extensive affinity-based selection. These long-lived MBCs appeared enriched in a CD21hiCD20hi IgG+ splenic B cell subset displaying a marginal-zone-like NOTCH/MYC-driven signature, but they did not harbor a unique longevity-associated transcriptional or metabolic profile. Finally, the telomeres of B5-specific, long-lived MBCs were longer than those in patient-paired naive B cells in all the samples analyzed. Overall, these results imply that separate mechanisms such as early telomere elongation, affinity selection during the contraction phase, and access to a specific niche contribute to ensuring the functional longevity of MBCs. [Display omitted] • Splenic vaccinia B5-specific MBCs can be isolated decades after last vaccination • Long-lived B5-specific MBCs display signs of extensive affinity-based selection • Long-lived B5-specific MBCs are enriched in a splenic CD21hiCD20hi IgG+ B cell subset • Long-lived B5-specific MBCs harbor long-lasting elongated telomeres Immune memory in humans has been shown to extend well beyond decades. Chappert et al. provide an extensive functional characterization of human splenic smallpox/vaccinia protein B5-specific MBCs, generated more than four decades ago, to decipher the distinct selection and survival mechanisms associated with MBCs longevity. [ABSTRACT FROM AUTHOR]

Lung-resident memory B cells (MBCs) provide localized protection against reinfection in respiratory airways. Currently, the biology of these cells remains largely unexplored. Here, we combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify MBCs regardless of antigen specificity. We found that two main transcriptionally distinct subsets of MBCs colonized the lung peribronchial niche after infection. These subsets arose from different progenitors and were both class switched, somatically mutated, and intrinsically biased in their differentiation fate toward plasma cells. Combined analysis of antigen specificity and B cell receptor repertoire segregated these subsets into "bona fide" virus-specific MBCs and "bystander" MBCs with no apparent specificity for eliciting viruses generated through an alternative permissive process. Thus, diverse transcriptional programs in MBCs are not linked to specific effector fates but rather to divergent strategies of the immune system to simultaneously provide rapid protection from reinfection while diversifying the initial B cell repertoire. [Display omitted] • Influenza and SARS-CoV-2 infection generates bona fide and bystander lung-resident MBCs • Bona fide and bystander MBC subsets differ in their origin and transcriptional programs • Bona fide MBCs are virus specific and produce antibody-secreting cells upon recall • Bystander MBCs are not virus specific but retain exogenous antigens as immune complexes Lung-resident memory B cells (MBCs) provide rapid protection against reinfection with airborne pathogens. Gregoire et al. demonstrate that two MBC subsets with discrete transcriptional programs reside in the lung peribronchial niche: "bona fide" virus-specific MBCs, which dominate recall responses, and "bystander" non-specific MBCs, which locally retain antigens as immune complexes. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals. [Display omitted] • Omicron evaded a large fraction of memory B cell (MBC)-derived antibodies • Only 30% of the MBCs retained high affinity against Omicron • Omicron neutralization by MBCs was reduced even more in all individuals • Neutralizing antibodies still represented more than 10% of the MBC repertoire Whether memory B cells (MBCs) elicited by SARS-CoV-2 mRNA vaccines can recognize the Omicron variant remains unclear. Sokal et al. show that compared with other variants of concern, Omicron evaded recognition and neutralization by a larger proportion of MBC-derived antibodies elicited after infection and/or vaccination. Nonetheless, Omicron-neutralizing MBC clones could be found in the repertoire of all the analyzed individuals. [ABSTRACT FROM AUTHOR]