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Adjuvants play pivotal roles in vaccine development, enhancing immunization efficacy through prolonged retention and sustained release of antigen, lymph node targeting, and regulation of dendritic cell activation. Adjuvant-induced activation of innate immunity is achieved via diverse mechanisms: for example, adjuvants can serve as direct ligands for pathogen recognition receptors or as inducers of cell stress and death, leading to the release of immunostimulatory-damage-associated molecular patterns. Adjuvant systems increasingly stimulate multiple innate pathways to induce greater potency. Increased understanding of the principles dictating adjuvant-induced innate immunity will subsequently lead to programming specific types of adaptive immune responses. This tailored optimization is fundamental to next-generation vaccines capable of inducing robust and sustained adaptive immune memory across different cohorts. A critical component of vaccine design is the immunogenicity of the adjuvant. Despite their importance, our understanding and development of optimal adjuvants remains in its infancy. Here, Lavelle and McEntee review the currently available adjuvants, their mechanisms of action, and future avenues toward advancing adjuvant innovations. [ABSTRACT FROM AUTHOR]

Disease-associated microglia (DAMs) are a unique microglial state in development and various CNS pathologies. In this issue of Immunity , Lan and colleagues provide novel insights into the diversity of DAMs in CNS diseases, revealing their terminal fate following juvenile stroke verses their reversible fate following neonatal stroke and their ability to maintain immune memory upon return to homeostatic states. [ABSTRACT FROM AUTHOR]

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]

The spike glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to accumulate substitutions, leading to breakthrough infections of vaccinated individuals. It remains unclear if exposures to antigenically distant SARS-CoV-2 variants can overcome memory B cell biases established by initial SARS-CoV-2 encounters. We determined the specificity and functionality of antibody and B cell responses following exposure to BA.5 and XBB variants in individuals who received ancestral SARS-CoV-2 mRNA vaccines. BA.5 exposures elicited antibody responses that targeted epitopes conserved between the BA.5 and ancestral spike. XBB exposures also elicited antibody responses that primarily targeted epitopes conserved between the XBB.1.5 and ancestral spike. However, unlike BA.5, a single XBB exposure elicited low frequencies of XBB.1.5-specific antibodies and B cells in some individuals. Pre-existing cross-reactive B cells and antibodies were correlated with stronger overall responses to XBB but weaker XBB-specific responses, suggesting that baseline immunity influences the activation of variant-specific SARS-CoV-2 responses. [Display omitted] • Variant breakthrough infections boost ancestral cross-reactive antibodies and B cells • First and second BA.5 exposures fail to elicit variant-specific antibodies and B cells • XBB infections and vaccinations elicit XBB-specific responses in some individuals • XBB-specific responses correlate with low levels of pre-existing humoral immunity It is unknown if antigenically distant SARS-CoV-2 variants can overcome memory B cell biases established by initial SARS-CoV-2 encounters. Johnston, Painter, Li et al. show that BA.5 and XBB exposures recall B cells targeting conserved epitopes in the ancestral SARS-CoV-2 spike protein. They found instances of XBB-specific responses after XBB exposures, which correlated with low baseline levels of humoral immunity. [ABSTRACT FROM AUTHOR]

Plasma cells that emerge after infection or vaccination exhibit heterogeneous lifespans; most survive for days to months, whereas others persist for decades, providing antigen-specific long-term protection. We developed a mathematical framework to explore the dynamics of plasma cell removal and its regulation by survival factors. Analyses of antibody persistence following hepatitis A and B and HPV vaccination revealed specific patterns of longevity and heterogeneity within and between responses, implying that this process is fine-tuned near a critical "flat" state between two dynamic regimes. This critical state reflects the tuning of rates of the underlying regulatory network and is highly sensitive to variation in parameters, which amplifies lifespan differences between cells. We propose that fine-tuning is the generic outcome of competition over shared survival signals, with a competition-based mechanism providing a unifying explanation for a wide range of experimental observations, including the dynamics of plasma cell accumulation and the effects of survival factor deletion. Our theory is testable, and we provide specific predictions. [Display omitted] • Plasma cells show extended lifespan in vivo with broad heterogeneity • Lifespan distribution and variation between antigens imply critical dynamics • Competition over survival factors self-tunes gene network to critical regime • Self-tuning by competition is beneficial for the long-term regulation of immune memory Plasma cells show remarkable longevity in vivo with broad heterogeneity between cells. By developing a minimal mathematical framework, Simons and Karin argue that the longevity and heterogeneity of plasma cell lifespan arise through the fine-tuning of gene regulatory networks to a critical regime driven by competition over survival factors in the niche. [ABSTRACT FROM AUTHOR]

Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（ Spp1 ） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1 + microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions. [Display omitted] • Spp1 + microglia exhibit context- and age-dependent heterogeneity in neuropathologies • Fate mapping of Spp1 + microglia reveals irreversible removal of DAM in juvenile stroke • Neonatal DAM exhibits remarkable plasticity and regain homeostasis as stroke resolves • Neonatal DAM retains immune memory and increased sensitivity to future immune insults The fate of disease-associated microglia (DAM) in neuropathologies remains elusive. Lan et al. generated an Spp1 fate-mapping model to track DAM-like microglia and find that the plasticity of DAM is age dependent. Juvenile stroke leads to the elimination of DAM, whereas neonatal DAM exhibits high plasticity and reversibility after injury, along with heightened sensitivity to subsequent immune challenges. [ABSTRACT FROM AUTHOR]

The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis -epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats. [Display omitted] • CD8+ T cell memory decisions occur early upon antigen encounter and after clearance • A reversible epigenetic switch controlling TCF1 enables flexible decision making • Switching is stochastic, generating heterogeneous outcomes within clonal lineages • Flexible decision making enables robust scaling of memory to infection severity When and how T cells make effector or memory decisions is not fully resolved. Abadie, Clark, and Valanparambil et al. uncover a reversible epigenetic switch enabling memory cells to diverge early after activation or dedifferentiate from effector cells later during antigen clearance. Thus, memory populations can scale with infection severity. [ABSTRACT FROM AUTHOR]

Immune responses are tightly regulated yet highly variable between individuals. To investigate human population variation of trained immunity, we immunized healthy individuals with Bacillus Calmette-Guérin (BCG). This live-attenuated vaccine induces not only an adaptive immune response against tuberculosis but also triggers innate immune activation and memory that are indicative of trained immunity. We established personal immune profiles and chromatin accessibility maps over a 90-day time course of BCG vaccination in 323 individuals. Our analysis uncovered genetic and epigenetic predictors of baseline immunity and immune response. BCG vaccination enhanced the innate immune response specifically in individuals with a dormant immune state at baseline, rather than providing a general boost of innate immunity. This study advances our understanding of BCG's heterologous immune-stimulatory effects and trained immunity in humans. Furthermore, it highlights the value of epigenetic cell states for connecting immune function with genotype and the environment. [Display omitted] • Clinical study with 323 healthy individuals over a 90-day time course of BCG vaccination • Time-resolved personal immune profiles, chromatin accessibility maps, and genotypes • Baseline immunity, seasonality, genotype, and chromatin predict trained immunity responses • Trained immunity is specific to individuals with a dormant innate immune state at baseline The response to vaccination and immune stimuli varies widely between individuals. To dissect population variation in immune function, Moorlag, Folkman, ter Horst, Krausgruber, et al. perform multi-omics analysis before and after BCG vaccination. They find that trained immunity induction is most effective in individuals with a dormant immune state at baseline. [ABSTRACT FROM AUTHOR]