(C) PLOS One This story was originally published by PLOS One and is unaltered. . . . . . . . . . . Age-associated B cells in viral infection [1] ['Isobel C. Mouat', 'Centre For Inflammation Research', 'University Of Edinburgh', 'Edinburgh', 'United Kingdom', 'Department Of Microbiology', 'Immunology', 'University Of British Columbia', 'Vancouver', 'British Columbia'] Date: 2022-07 Age-associated B cells (ABCs) are a recently identified, unique B cell population that displays both protective and pathogenic characteristics, depending on the context. A major role of ABCs is to protect from viral infection. ABCs expand during an array of viral infections and display various functional capacities, including secretion of antibodies and activation of T cells. Following resolution of infection, ABCs appear to persist and play a crucial role in memory and recall responses. Here, we review the currently understanding of ABCs in the antiviral response in both humans and mice. We discuss avenues for future research, including the impact of sex on the ABC population and heterogeneity of ABCs between contexts. Funding: We gratefully acknowledge support from the MS Society of Canada (MSSC – 3631, MSH) and Canadian Institutes of Health Research (CIHR - PJT – 178298, MSH & ICM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2022 Mouat, Horwitz. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction A unique B cell population, termed age-associated B cells (ABCs), was identified in 2011 in the contexts of aging and autoimmunity [1,2]. The frequency of ABCs increases with age, particularly in females, and is elevated during various autoimmune and autoinflammatory diseases [3]. ABCs express the transcription factor T-bet, which has been well characterized in various infections [4]. Recently, B cells broadly expressing T-bet have received much attention in potentiating antiviral immune responses, and, accordingly, it has since been shown that ABCs do in fact respond to an array of viral infections (Table 1). ABCs, atypical memory B cells, and T-bet+ B cells are all names used to describe what is likely a similar population, with primary markers used to denote the population including high expression of both CD11c and T-bet and low expression of CD21. The precise contribution(s) of ABCs to health and disease continues to be examined. PPT PowerPoint slide PNG larger image TIFF original image Download: Table 1. ABCs are expanded in an array of viral infections and vaccinations. The relative proportion of ABCs is increased following various viral infections as measured by the cell markers listed and vaccinations in both mice and humans and are found at multiple anatomical locations. https://doi.org/10.1371/journal.ppat.1010297.t001 The frequency of ABCs has been shown to increase in various viral infections in humans and mice, including hepatitis C virus (HCV), rhinovirus, human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, lymphocytic choriomeningitis virus (LCMV), vaccinia, murine cytomegalovirus (MCMV), and gammaherpesvirus-68 (γHV68) [5–13] (Table 1). The proportion of circulating ABCs is also increased following several vaccinations in people, including those for influenza [14,15], yellow fever [7], and vaccinia [7] (Table 1). ABCs are a major population of virus-specific B cells during infection and following vaccination [6–8,10,14,16]. In individuals with HIV, nearly all of the B cells specific to HIV envelope glycoprotein gp140 in the peripheral blood are ABCs [7]. Following influenza infection in mice, the majority of virus-specific B cells in the lungs are ABCs 15 days postinfection, and one-third of virus-specific B cells in the spleen are ABCs 100 days postinfection [10]. Following influenza vaccination, a significantly higher proportion of ABCs are specific for the influenza surface protein hemagglutinin compared to classical memory B cells [14]. Evidence suggests that ABCs are long-lived effector B cells that display memory characteristics and are poised to differentiate into an antibody-secreting cell upon challenge [14]. ABCs display distinct activation requirements, transcriptional profile, and localization patterns compared to other B cell subsets [1,2,10]. Their enrichment for antigen specificity as well as persistence and effector functional capacities indicate that ABCs likely play an important role during and following viral infections (Box 1). There is much to be learned about this unique population during health, infection, and disease. Here, we briefly review what is currently known about the role of ABCs in viral infections and discuss possibilities for future investigations. Box 1. Learning points Age-associated B cells (ABCs) increase during viral infection and following vaccination. Following infection, ABCs remain elevated long term and are important for robust recall responses. ABCs secrete antiviral antibodies and cytokines and stimulate T cells. How antiviral ABCs relate to ABCs during autoimmune disease and aging remains incompletely understood. Anatomical distribution During acute or active viral infection, ABCs expand both in the spleen and at the site of infection (Fig 1 and Table 1). In both humans and mice, influenza infection results in increased ABC frequency in the lungs and the mediastinal lymph nodes (LNs), in addition to the spleen [10]. In individuals with HIV viremia, ABCs expand in LNs [8], and during rhinovirus infection, ABCs are elevated in the blood and nasal tissue [6]. The frequency of ABCs then decreases at the site of infection following its resolution. After clearance of acute influenza infection in mice, the number and proportions of ABCs is decreased in the lung, mediastinal LNs, and blood, as compared to active infection [10]. In individuals with HCV, the frequency of circulating ABCs is significantly decreased following antiviral treatment and clearance of the infection, compared to the frequency at the onset of treatment [5]. PPT PowerPoint slide PNG larger image TIFF original image Download: Fig 1. ABCs in acute infection and recall response. During acute viral infection, ABCs are increased at the site of infection, in circulation, and in the spleen, and are largely antigen specific. Following clearance of acute infection, ABCs primarily reside in the spleen and differentiate into antibody-secreting cells upon rechallenge. The figure was created using BioRender.com. ABC, age-associated B cell; ASC, antibody-secreting cell. https://doi.org/10.1371/journal.ppat.1010297.g001 Current evidence suggests that ABCs are predominantly maintained in the spleen following resolution of infection (Fig 1). ABCs remain in the spleen at an elevated frequency long-term (100+ days) in mice infected with influenza compared to naïve mice [10]. Mouse parabiosis experiments demonstrate that antigen-specific ABCs are spleen resident and do not circulate systemically during steady state conditions [10]. The anatomical distribution of these ABCs primarily residing in the spleen during homeostasis appears largely conserved between mice and humans; in healthy individuals, ABCs are typically found in the spleen and bone marrow, though also at low numbers in tonsils and LNs [10]. Collectively, these studies indicate that the frequency of ABCs is increased in the spleen and at the site of disease during ongoing infection and that ABCs persist primarily in the spleen following clearance. Differentiation The signals that stimulate ABC differentiation are induced via the synergistic engagement of various cytokine and antigenic receptors that are activated during viral infection, including the interferon gamma (IFNγ) receptor, Toll-like receptor 7 (TLR7), and the B cell receptor [13,17–22]. It has not been conclusively determined from which B cell populations ABCs arise. While follicular B cells have been shown to be able to differentiate into ABC-like cells under appropriate conditions ex vivo [23], other subsets, including marginal zone or transitional B cells, could also contribute to the ABC pool in vivo. ABCs display diversity in germ line V H and Vκ genes, indicating they are not a single clonally expanded population, but rather arise through an antigen-driven B cell response from an array of common naïve B cells [24]. It was originally believed that ABCs originate through an antigen-driven germinal center (GC) response, as they display somatically mutated heavy and light chains and isotype switching [24]. However, somatic hypermutation and class-switch recombination is known to take place outside of the GC [25–27]. Recent evidence indicates that ABCs can arise outside of the GC. Fate mapping studies have shown that a portion of ABCs are not GC-derived [28]. B cells outside of the GC express elevated phosphorylated signal transducer and activator of transcription 1 (pSTAT1), upstream of T-bet expression, in B cells [17], indicating that T-bet is likely up-regulated in B cells prior to GC entry [11]. It is possible, and has been previously suggested, that ABCs might undergo different differentiation processes and could arise from both within and outside of the GC [3]. Moving forward, fate mapping and imaging techniques will be important for determining the origination and precise anatomical localization of ABCs. Functions of ABCs during primary viral responses ABCs display various functional capacities during viral infections, including antibody and cytokine production and interaction with T cells (Table 2). The production of antiviral antibodies is likely a major way in which ABCs contribute to the control of viral infections. T-bet expression in mouse B cells is required for IgG2a/c class switching and ABCs are enriched for IgG2a/c [29,30]. IgG2a/c (IgG1 in humans) is associated with a Th1 response and is the major antiviral isotype [31,32]. Knocking out ABCs in mice leads to a significant decrease in IgG2a/c titers [11–13], and transfer of virus-specific antibodies into mice deficient in ABCs is able to partially restore control of chronic LCMV [12]. PPT PowerPoint slide PNG larger image TIFF original image Download: Table 2. ABCs display multiple functional capacities during viral infections. https://doi.org/10.1371/journal.ppat.1010297.t002 B cells also contribute to antiviral immunity through mechanisms other than antibody production, including cytokine secretion and presentation of antigen to T cells [39]. ABCs secrete an array of cytokines with substantial production of IFNγ, tumor necrosis factor (TNF), and interleukin 6 (IL-6) [33–35]. ABCs express more IL-6 and TNF than follicular B cells, and ABC production of IL-6 and TNF is increased in old mice (18 to 22 months) compared to young mice (3 to 4 months) [35]. ABCs can interact with and stimulate T cells [11,38], though whether ABCs are acting as primary antigen-presenting cells or are reactivating T cells in a paracrine manner is less clear. Most evidence of ABC interaction with T cells comes from studies in the contexts of inflammatory and autoimmune diseases, rather than viral infection. In individuals with Crohn’s disease, T-bet+ B cell numbers correlate with IFNγ+ T cell numbers in the gut [40]. Further, culturing ABC-like cells from individuals with Crohn’s disease with autologous CD4+ T cells results in the production of IFNγ and IL-12 by the T cells [40]. This result highlights a role for ABCs in stimulating inflammatory T cells and suggests this as a possible way in which ABCs could contribute to disease. Similarly, systemic lupus erythematosus (SLE) mice without ABCs display defects in T cells, with fewer activated/memory CD4+ T cells and less IFNγ+CD8+ T cells compared to mice with ABCs [41]. Coculturing ABC-like cells from mice with autoimmune experimental hepatitis with CD4+ T cells resulted in impaired T cell proliferation and decreased IFNγ production [42]. In contrast, our group and others have reported no differences in IFNγ production by T cells between mice with and without ABCs during chronic LCMV and latent γHV68 infections [12,37]. During influenza infection CD11c+ B cells localize to the T cell–B cell boundary in the spleen and more efficiently present antigen than follicular B cells [11]. Although ABCs are capable of various antiviral functions, including antibody and cytokine secretion and antigen presentation to T cells, the relative contributions of these responses during and after viral infection are unclear and deserve further study. 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