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Existing antibodies (Abs) have varied effects on humoral immunity during subsequent infections. Here, we leveraged in vivo systems that allow precise control of antigen-specific Abs and B cells to examine the impact of Ab dose, affinity, and specificity in directing B cell activation and differentiation. Abs competing with the B cell receptor (BCR) epitope showed affinity-dependent suppression. By contrast, Abs targeting a complementary epitope, not overlapping with the BCR, shifted B cell differentiation toward Ab-secreting cells. Such Abs allowed for potent germinal center (GC) responses to otherwise poorly immunogenic sites by promoting antigen capture and presentation by low-affinity B cells. These mechanisms jointly diversified the B cell repertoire by facilitating the recruitment of high- and low-affinity B cells into Ab-secreting cell, GC, and memory B cell fates. Incorporation of small amounts of monoclonal Abs into protein- or mRNA-based vaccines enhanced immunogenicity and facilitated sustained immune responses, with implications for vaccine design and our understanding of protective immunity. [Display omitted] • Dose- and affinity-dependent implications of antibody (Ab)-mediated epitope masking • Abs promote the Ab-secreting cell fate of B cells recognizing non-overlapping epitopes • Small amounts of non-competitive Abs enhance low-affinity B cell responses, including GCs • Abs as adjuvants for recombinant protein- and mRNA-based vaccines Antibodies that protect us from pathogens also influence how the immune system responds to infection or vaccination. Dvorscek et al. reveal a mechanistic framework of how antibodies can optimize protective immunity, regulating B cell response participation and duration in a way that can be harnessed for vaccine design. [ABSTRACT FROM AUTHOR]

Antibodies produced by antibody-secreting plasma cells (ASCs) underlie multiple forms of long-lasting immunity. Here we examined the mechanisms regulating ASC turnover and persistence using a genetic reporter to time-stamp ASCs. This approach revealed ASC lifespans as heterogeneous and falling on a continuum, with only a small fraction surviving for >60 days. ASC longevity past 60 days was independent of isotype but correlated with a phenotype that developed progressively and ultimately associated with an underlying "long-lived" ASC (LL ASC)-enriched transcriptional program. While some of the differences between LL ASCs and other ASCs appeared to be acquired with age, other features were shared with some younger ASCs, such as high CD138 and CD93. Turnover was unaffected by altered ASC production, arguing against competition for niches as a major driver of turnover. Thus, ASC turnover is set by intrinsic lifespan limits, with steady-state population dynamics governed by niche vacancy rather than displacement. [Display omitted] • Homeostatic plasma cell (PC) turnover was quantified using a genetic time stamp • Long-lived PCs are enriched for a gene signature and pattern of surface markers • In ontogeny, markers of longevity are acquired with PC age • Homeostatic turnover is driven largely by intrinsic death and not by niche competition Plasma cell (PC) longevity is a key determinant of long-lasting immunity. Robinson, Ding, et al. develop a genetic time-stamping approach to quantify homeostatic PC turnover and uniquely identify those cells that are long-lived in bone marrow and spleen. Such PCs are enriched for a gene signature and cell-surface phenotype, with their turnover determined intrinsically and not by niche competition. [ABSTRACT FROM AUTHOR]

Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo , we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4+ T cell expansion and differentiation in a dose-dependent manner and with paracrine activity. Within GC, IL-21 specifically promoted B cell centroblast identity and, when bioavailability was high, plasma cell differentiation. Critically, these actions may occur irrespective of cognate T-B interactions, making IL-21 a general promoter of growth as distinct to a mediator of affinity-driven selection via synaptic delivery. This promiscuous activity of IL-21 explains the consequences of IL-21 deficiency on antibody-based immunity. [Display omitted] • Paracrine IL-21 promotes CD4+ T cell expansion, differentiation, and IL-21 production • Initial germinal center magnitude depends on Tfh numbers and IL-21 • IL-21 maintains germinal center B cells irrespective of the cognate T-B synapse • IL-21 bioavailability regulates dark zone CB identity and plasma cell differentiation The formation and maintenance of germinal centers is fundamental to humoral immunity and requires interleukin 21 (IL-21). Quast et al. show that IL-21 independently regulates germinal center T and B cells and that its effects occur in paracrine, related to amount and outside the confines of the T-B synapse. [ABSTRACT FROM AUTHOR]

The transcription factor interferon regulatory factor 4 (IRF4) is critical for the development, maintenance, and function of plasma cells. The mechanism by which IRF4 exerts its action in mature plasma cells has been elusive due to the death of all such cells upon IRF4 loss. While we identify apoptosis as a critical pathway for the death of plasma cells caused by IRF4 loss, we also determine that IRF4 did not regulate the intrinsic apoptotic pathway directly. By using an inducible IRF4 deletion system in the presence of the overexpression of anti-apoptotic BCL2, we identify genes whose expression is coordinated by IRF4 and that in turn specify plasma cell identity and mitochondrial homeostasis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Humoral immune responses are tailored to the invading pathogen through regulation of key transcription factors and their networks. This is critical to establishing effective antibody-mediated responses, yet it is unknown how B cells integrate pathogen-induced signals to drive or suppress transcriptional programs specialized for each class of pathogen. Here, we detail the key role of the transcription factor c-Myb in regulating the T-bet-mediated anti-viral program. Deletion of c-Myb in mature B cells significantly increased serum IgG2c and CXCR3 expression by upregulating T-bet, normally suppressed during Th2-cell-mediated responses. Enhanced expression of T-bet resulted in aberrant plasma cell differentiation within the germinal center, mediated by CXCR3 expression. These findings identify a dual role for c-Myb in limiting inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Identifying such intrinsic regulators of specialized antibody responses can assist in vaccine design and therapeutic intervention in B-cell-mediated immune disorders., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)