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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]

The generation of anti-tumor immunity in the draining lymph nodes is known as the cancer immunity cycle. Accumulating evidence supports the occurrence of such a cycle at tumor sites in the context of chronic inflammation. Here, we review the role of tertiary lymphoid structures (TLS) in the generation of T and B cell immunities, focusing on the impact of B cells that undergo full maturation, resulting in the generation of plasma cells (PCs) producing high-affinity IgG and IgA antibodies. In this context, we propose that antibodies binding to tumor cells induce macrophage or natural killer (NK)-cell-dependent apoptosis. Subsequently, released antigen-antibody complexes are internalized and processed by dendritic cells (DCs), amplifying antigen presentation to T cells. Immune complexes may also be fixed by follicular DCs (FDCs) in TLS, thereby increasing memory B cell responses. This amplification loop creates an intra-tumoral immunity cycle, capable of increasing sensitivity of tumors to immunotherapy even in cancers with low mutational burden. Fridman and colleagues review the role of tertiary lymphoid structures in the generation of T and B cell immunities in the context of cancer. Integrating insights from basic research and the clinic, the authors propose a role for antibodies in a loop that amplifies anti-tumor immunity within the tumor. [ABSTRACT FROM AUTHOR]

Memory T cells comprise circulating and tissue-resident subsets. In this issue of Immunity , Evrard et al. generate an imputed high-dimensional, single-cell protein expression atlas of memory CD8+ T cells, providing insights into stable differentiation markers and organ-specific expression patterns. [ABSTRACT FROM AUTHOR]

In the past few decades, a number of transformative discoveries have been made regarding memory CD8+ T cell biology; meanwhile, the CD4+ T cell field has lagged behind this progress. This perspective focuses on CD4+ helper T (Th) cell subset specification and memory cell formation. Here, we argue that the sheer number of Th effector and memory cell subsets and a focus on their differences have been a barrier to a general model of CD4+ memory T cell formation that applies to all immune responses. We highlight a bifurcation model that relies on an IL-2 signal-dependent switch as an explanation for the balanced production of diverse Th memory cells that participate in cell-mediated or humoral immunity in most contexts. Our understanding of CD4+ T cell biology currently suffers from a divergence between helper subset differentiation and memory formation. In this perspective, Jenkins and colleagues propose an integrative model broadly incorporating the concepts of Th1/Th2 differentiation, central and effector memory formation, and cellular and humoral immunity. [ABSTRACT FROM AUTHOR]

Immune memory develops during primary infections to protect from future exposures to the same pathogen. Vaccines mimic this response and induce immune memory that protects from severe disease and, in some cases, from symptomatic infection. If the pathogen is eliminated before it can replicate, natural and vaccine-induced immune memory can prevent the establishment of the infection, mediating sterilizing immunity. Sterilizing immunity protects the individual and prevents transmission to new hosts, thereby contributing to protection at a population level. Here, we describe the basic concepts of sterilizing immunity and discuss its relevance for protection in the context of SARS-CoV-2. Sterilizing immunity describes the elimination of a pathogen before it can replicate in the host. Here, Wahl and Wardemann describe the challenges of inducing and measuring sterilizing immunity. The authors discuss the relevance of sterilizing immunity for protection in the context of the ongoing SARS-CoV-2 pandemic and COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

T cell responses against foreign antigens are clonally diverse, but the significance of this diversity is unclear. In this issue of Immunity , Straub et al. 1 show that recruitment of low-avidity T cells during primary infection can provide protection against subsequent encounter with escape variants. T cell responses against foreign antigens are clonally diverse, but the significance of this diversity is unclear. In this issue of Immunity , Straub et al. show that recruitment of low-avidity T cells during primary infection can provide protection against subsequent encounter with escape variants. [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]

Many aspects of SARS-CoV-2 have fully conformed with the principles established by decades of viral immunology research, ultimately leading to the crowning achievement of highly effective COVID-19 vaccines. Nonetheless, the pandemic has also exposed areas where our fundamental knowledge is thinner. Some key unknowns are the duration of humoral immunity post-primary infection or vaccination and how long booster shots confer protection. As a corollary, if protection does not last as long as desired, what are some ways it can be improved? Here, I discuss lessons from other infections and vaccines that point to several key features that influence durable antibody production and the perseverance of immunity. These include (1) the specific innate sensors that are initially triggered, (2) the kinetics of antigen delivery and persistence, (3) the starting B cell receptor (BCR) avidity and antigen valency, and (4) the memory B cell subsets that are recalled by boosters. I further highlight the fundamental B cell-intrinsic and B cell-extrinsic pathways that, if understood better, would provide a rational framework for vaccines to reliably provide durable immunity. The efficacies of COVID-19 vaccines have decreased over time and as new variants have emerged. Bhattacharya discusses basic plasma cell biology, the features of vaccines that influence the duration of antibody production, and possible paths to lasting immunity against COVID-19. [ABSTRACT FROM AUTHOR]

Neuroanatomical barriers with physical, chemical, and immunological properties play an essential role in preventing the spread of peripheral infections into the CNS. A failure to contain pathogens within these barriers can result in very serious CNS diseases. CNS barriers are inhabited by an elaborate conglomerate of innate and adaptive immune cells that are highly responsive to environmental challenges. The CNS and its barriers can also be protected by memory T and B cells elicited by prior infection or vaccination. Here, we discuss the different CNS barriers from a developmental, anatomical, and immunological standpoint and summarize our current understanding of how memory cells protect the CNS compartment. We then discuss a contemporary challenge to CNS-barrier system (SARS-CoV-2 infection) and highlight approaches to promote immunological protection of the CNS via vaccination. Neuroanatomical barriers are defended by the immune system to safeguard the CNS parenchyma from pathogens. Ampie and McGavern review the anatomy and development of CNS barriers as well as their immunological composition during steady state and in response to infections. They also explore how to protect these barriers via vaccination and then discuss the immunology and neuropathogenesis of a contemporary CNS challenge (i.e., SARS-CoV-2). [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]

Metastatic ovarian cancer is a significant clinical challenge due in part to its poor response to immunotherapy. In a recent issue of Cancer Cell , Anandon et al. (2022) identify a population of stem-like tissue-resident memory T cells that are responsible for the bulk of anti-tumor T cell immunity, with insights into improving therapeutic response. Metastatic ovarian cancer is a significant clinical challenge due in part to its poor response to immunotherapy. In a recent issue of Cancer Cell , Anandon et al. (2022) identify a population of stem-like tissue resident memory T cells that are responsible for the bulk of anti-tumor T cell immunity, with insights into improving therapeutic response. [ABSTRACT FROM AUTHOR]

Immunological memory is a mechanism to protect us against reinfection. Antibodies produced by B cells are integral to this defense strategy and underlie virtually all vaccine success. Here, we explain how B cells memory is generated by infection and vaccination, what influences its efficacy and its persistence, and how characterizing these parameters in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will help achieve protective immunity through vaccination. [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]

Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25–85 years old. From this, we generated a dataset from ∼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZMK +CD8+ T cells and HLA-DR +CD4+ T cells. In contrast to other T cell memory subsets, transcriptionally distinct NKG2C + GZMB − CD8+ T cells counterintuitively decreased with age. Furthermore, we found a concerted age-associated increase in type 2/interleukin (IL)4-expressing memory subpopulations across CD4+ and CD8+ T cell compartments (CCR4 +CD8+ Tcm and Th2 CD4+ Tmem), suggesting a systematic functional shift in immune homeostasis with age. Our work provides novel insights into healthy human aging and a comprehensive annotated resource. [Display omitted] • Clinical and scRNA-seq data of 2 million PBMCs from 166 people aged 25–85 years old • Type 2 memory CD4+ and CD8+ T cells increase with age and can produce more IL-4 • NKG2C+GZMB–XCL1+ defines a unique memory CD8+ T cell subset that decreases with age • HLA-DR+ CD4+ memory T cells and GZMK+ CD8+ T cells accumulate with age Terekhova et al. perform single-cell RNA sequencing on >300 samples between 25 and 85 years to comprehensively profile immune changes throughout aging. This resource revealed 12 subpopulations that change with age, including increased type 2 memory CD4+ and CD8+ T cells and decreased NKG2C+GZMB−CD8+ memory population. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) can cause severe diseases in fetuses, newborns, and immunocompromised individuals. Currently, no vaccines are approved, and treatment options are limited. Here, we analyzed the human B cell response of four HCMV top neutralizers from a cohort of 9,000 individuals. By single-cell analyses of memory B cells targeting the pentameric and trimeric HCMV surface complexes, we identified vulnerable sites on the shared gH/gL subunits as well as complex-specific subunits UL 128/130/131A and gO. Using high-resolution cryogenic electron microscopy, we revealed the structural basis of the neutralization mechanisms of antibodies targeting various binding sites. Moreover, we identified highly potent antibodies that neutralized a broad spectrum of HCMV strains, including primary clinical isolates, that outperform known antibodies used in clinical trials. Our study provides a deep understanding of the mechanisms of HCMV neutralization and identifies promising antibody candidates to prevent and treat HCMV infection. [Display omitted] • Analysis of HCMV-reactive memory B cells in top neutralizers identifies potent nAbs • Epitope mapping uncovers vulnerable sites on the HCMV Trimer and Pentamer • A gO-targeting nAb prevents infection of fibroblasts, epithelial, and endothelial cells • Cryo-EM structures provide functional understanding of antibody neutralization Vaccines against HCMV are not available, and treatment options are limited. By dissecting the B cell response of HCMV top neutralizers, Zehner et al. reveal key epitopes for the neutralization of HCMV. Structural analyses elucidate HCMV neutralization mechanisms, and highly potent and cross-neutralizing antibodies were identified. These data provide a basis for developing antibody-mediated approaches to effectively prevent and treat HCMV infection. [ABSTRACT FROM AUTHOR]

The generation of memory B cells and plasma cells is complex and involves inputs from the microenvironment, notably from T follicular helper cells. In last month's issue of Immunity , Yeh et al. and Song et al. refine our understanding of the B cell intrinsic and extrinsic requirements to generate effective humoral immunity in response to foreign antigens. [ABSTRACT FROM AUTHOR]

The last few years have witnessed an increasing body of evidence that challenges the traditional view that immunological memory is an exclusive trait of the adaptive immune system. Myeloid cells can show increased responsiveness upon subsequent stimulation with the same or a different stimulus, well after the initial challenge. This de facto innate immune memory has been termed "trained immunity" and is involved in infections, vaccination and inflammatory diseases. Trained immunity is based on two main pillars: the epigenetic and metabolic reprogramming of cells. In this review we discuss the latest insights into the epigenetic mechanisms behind the induction of trained immunity, as well as the role of different cellular metabolites and metabolic networks in the induction, regulation and maintenance of trained immunity. Recent advances in the field of innate immunity have revealed the mechanisms of trained immunity (innate immune memory): namely the epigenetic and metabolic reprogramming of cells. Fanucchi et al. review these advances with deeper insight into the roles of noncoding RNA and genome architecture in the "writing" of trained immunity. [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]

Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated in substantial changes in the corresponding antibody response. A major source of antigen format-related variability was the ability to recruit naive vs. memory B and T cells to the response. These findings have important implications for vaccine design and the generation of protective immune responses in the upper respiratory tract. [Display omitted] • Used tonsil organoids to compare influenza vaccine formats within an individual • Transcriptional fate of Ag-specific B cells is affected by vaccine format • Type I IFNs mediate some but not all of the vaccine-format-specific differences • Inactivated flu vaccine depends on pre-existing memory cells Understanding the cellular dynamics underlying responses to different antigen formats is critical for rational vaccine design. Using a human immune organoid model, Kastenschmidt et al. evaluate the effect of influenza vaccine modalities on adaptive immunity and reveal key differences in the magnitude, breadth, and quality of B cell, T cell, and antibody responses. [ABSTRACT FROM AUTHOR]

Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0–10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children. [Display omitted] • Memory T cells preferentially accumulate in human mucosal tissues during early life • T RM cells undergo functional maturation over childhood • T RM cells exhibit distinct transcriptional programs and site-specific expansion over age Immune memory generation during early childhood is critical for long-term protective immunity. Connors et al. analyze the development of human memory T cells in lymphoid organs, mucosal sites, and blood over infancy and childhood. Memory T cells accumulate rapidly in the intestines and lungs and display age- and tissue-driven maturation stages. [ABSTRACT FROM AUTHOR]

Memory CD8+ T cells can be broadly divided into circulating (T CIRCM) and tissue-resident memory T (T RM) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of T CIRCM and T RM cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and machine learning prediction pipeline (InfinityFlow) to profile >200 proteins in T CIRCM and T RM cells in solid organs and barrier locations. High-dimensional analyses revealed unappreciated heterogeneity within T CIRCM and T RM cell lineages across nine different organs after either local or systemic murine infection models. Additionally, we demonstrated the relative effectiveness of strategies allowing for the selective ablation of T CIRCM or T RM populations across organs and identified CD55, KLRG1, CXCR6, and CD38 as stable markers for characterizing memory T cell function during inflammation. Together, these data and analytical framework provide an in-depth resource for memory T cell classification in both steady-state and inflammatory conditions. [Display omitted] • InfinityFlow profiling of CD8+ T cells across tissues and infection models • Resolution of T CIRCM and T RM cell-specific phenotypes across different organs • Development of tissue-specific T CIRCM or T RM cell depletion strategies • Discovery of stable markers for T CIRCM and T RM cell functional characterization Distinguishing between circulating (T CIRCM) and tissue-resident memory T (T RM) cells is challenging, particularly in tissues where they coexist. By profiling hundreds of surface proteins at the single-cell level, Evrard et al. reveal markers allowing the identification, targeted depletion, and functional characterization of T CIRCM and T RM populations across tissues and infection contexts. [ABSTRACT FROM AUTHOR]

CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states. [Display omitted] • ARID1A-containing cBAF opens enhancers in effector CD8+ T cells during infection • cBAF establishes binding sites of many effector TFs, including T-bet and BATF • cBAF is necessary for late-stage differentiation of TE and Trm cells • Circulating memory cells form without cBAF, but are functionally impaired Chromatin remodeling is a critical step for cellular differentiation. McDonald et al. show that the canonical BAF complex mediates chromatin remodeling to establish de novo enhancers in recently activated virus-specific CD8+ T cells, which, in turn, allows the activated cells to acquire specialized effector and memory cell fates. [ABSTRACT FROM AUTHOR]

Repetitive pathogen exposure leads to the dominant outgrowth of T cell clones with high T cell receptor (TCR) affinity to the relevant pathogen-associated antigens. However, low-affinity clones are also known to expand and form immunological memory. While these low-affinity clones contribute less immunity to the original pathogen, their role in protection against pathogens harboring immune escape mutations remains unclear. Based on identification of the TCR repertoire and functionality landscape of naive epitope-specific CD8+ T cells, we reconstructed defined repertoires that could be followed as polyclonal populations during immune responses in vivo. We found that selective clonal expansion is governed by clear TCR avidity thresholds. Simultaneously, initial recruitment of broad TCR repertoires provided a polyclonal niche from which flexible secondary responses to mutant epitopes could be recalled. Elucidating how T cell responses develop "from scratch" is informative for the development of enhanced immunotherapies and vaccines. [Display omitted] • TCR avidity distribution in naive donors is highly skewed • Clonal T cell expansion upon infection is governed by clear TCR avidity thresholds • The cross-reactivity landscape of single TCRs correlates with functional avidity • Recruitment of broad TCR repertoires enables flexible immune responses High-avidity CD8+ T cells provide protective immunity. However, their recruitment into immune responses alongside lower avidity T cells is not well understood. Straub et al. here show that rare high-avidity clones are selectively expanded from naive precursor repertoires with heterogeneous functionalities. Such polyclonal recruitment enables flexible immune responses against heterologous re-infection. [ABSTRACT FROM AUTHOR]

Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8+ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8+ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8+ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8+ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome. [Display omitted] • Genome organization changes with effector CD8+ T cell differentiation • CTCF-binding patterns are altered with effector CD8+ T cell differentiation • CTCF regulates subset-specific transcriptional programs and chromatin accessibility • CTCF controls optimal CD8+ T cell-fate decisions in response to infection How changes in spatial chromatin organization are integrated into the network of molecular mechanisms mediating CD8+ T cell effector functions and memory formation is not well understood. Quon et al. characterize genome interactions accompanying the CD8+ T cell response to infection and find that the DNA architectural protein, CTCF, regulates the balance of terminally differentiated-effector cells and memory-fated 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]

Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections. [Display omitted] • Breakthrough infection elicits a rapid recall of CD4+ and CD8+ spike-specific T cells • CD4+ T cell recall is robust and coordinated, peaking by day 5 post symptoms • CD8+ T cells become activated but variably expand following infection • Spike-specific CD8+ T cell activation inversely correlates with the rate of viral decay Our understanding of T cell responses to SARS-CoV-2 vaccination and breakthrough infection has lagged behind B cells and antibodies. Here, Koutsakos et al. utilize longitudinal sampling to demonstrate a rapid activation of SARS-CoV-2-specific CD4+ and CD8+ T cells during breakthrough infection. Furthermore, spike-specific CD8+ T cell activation correlates with viral clearance. [ABSTRACT FROM AUTHOR]

Summary Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8 + T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency. Polycomb repressive complex 2 deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8 + memory T cell maturation. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, probably from diminished transcription factor FOXO1 expression. These results outline a temporal model for loss of memory cell potential through selective epigenetic silencing of pro-memory genes in effector T cells. [ABSTRACT FROM AUTHOR]

Tissue-resident memory CD8+ T (T RM) cells are a subset of memory T cells that play a critical role in limiting early pathogen spread and controlling infection. T RM cells exhibit differences across tissues, but their potential heterogeneity among distinct anatomic compartments within the small intestine and colon has not been well recognized. Here, by analyzing T RM cells from the lamina propria and epithelial compartments of the small intestine and colon, we showed that intestinal T RM cells exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional, epigenetic, and functional heterogeneity. The T-box transcription factor Eomes, which represses T RM cell formation in some tissues, exhibited unexpected context-specific regulatory roles in supporting the maintenance of established T RM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of intestinal T RM cells. [Display omitted] • Small intestine (SI) and colon CD8+ T RM cells are molecularly and functionally distinct • Anatomically distinct SI T RM cells exhibit disparate degrees of developmental plasticity • Eomes supports maintenance of established T RM cells in the SI, but not in the colon • Eomes promotes expression of the anti-apoptotic regulator Bcl-2 The tissue- and context-specific regulation of tissue-resident memory T (T RM) cells, which provide protection in organs and at barrier sites, is an emerging concept. Lin et al. show that CD8+ T RM cells from the SI vs. the colon exhibit unique molecular and functional attributes along with distinct transcriptional requirements for their maintenance. [ABSTRACT FROM AUTHOR]

T memory stem cells (T SCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. T SCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8+ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced T SCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to T SCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy. [Display omitted] • UA induces Pink1-dependent mitophagy in CD8+ cells causing PGAM5 release • Cytosolic PGAM5 augments Wnt signaling to drive T SCM formation • T SCM induction augments anti-tumor immunity in vivo • Urolithin can be used for ex vivo expansion of CAR-expressing T SCM Anti-tumor immunity is limited by reduced T cell persistence and antigen presentation. Denk et al. show that Urolithin A, a natural metabolite of pomegranate extract, enhances antigen presentation in cancer and promotes mitophagy in CD8+ T cells, resulting in generation regenerative stem cell-like memory (T SCM) cells with enhanced anti-tumor properties. [ABSTRACT FROM AUTHOR]

The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing stratified murine adult B cells based on the timing of output, revealing that a substantial portion originated within a restricted neonatal window. In addition to B-1a cells, early-life time-stamped B cells included clonally interrelated IgA plasma cells in the gut and bone marrow. These were actively maintained by B cell memory within gut chronic germinal centers and contained commensal microbiota reactivity. Neonatal rotavirus infection recruited recurrent IgA clones that were distinct from those arising by infection with the same antigen in adults. Finally, gut IgA plasma cells arose from the same hematopoietic progenitors as B-1a cells during ontogeny. Thus, a complex layer of neonatally imprinted B cells confer unique antibody responses later in life. [Display omitted] • Lineage tracing reveals substantial neonatal contribution to the adult B cell pool • Adult IgA PCs are actively maintained by early-life-induced memory • Neonatal IgA memory harbors unique recurrent clonotypes not generated in the adult • B-1a cells and IgA PCs stem from a common progenitor pool during ontogeny Vergani et al. use time-stamping to examine the relationship between developmental origin and the composition of the adult B cell pool. They find that B cells arising early in life substantially contribute to the IgM and IgA repertoires in unimmunized adult mice. These early-life-origin B cells form a network of self-sustaining IgA memory compartments that archive unique specificities not generated later in life. [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]

SARS-CoV-2 infection and vaccination generates enormous host-response heterogeneity and an age-dependent loss of immune-response quality. How the pre-exposure T cell repertoire contributes to this heterogeneity is poorly understood. We combined analysis of SARS-CoV-2-specific CD4+ T cells pre- and post-vaccination with longitudinal T cell receptor tracking. We identified strong pre-exposure T cell variability that correlated with subsequent immune-response quality and age. High-quality responses, defined by strong expansion of high-avidity spike-specific T cells, high interleukin-21 production, and specific immunoglobulin G, depended on an intact naive repertoire and exclusion of pre-existing memory T cells. In the elderly, T cell expansion from both compartments was severely compromised. Our results reveal that an intrinsic defect of the CD4+ T cell repertoire causes the age-dependent decline of immune-response quality against SARS-CoV-2 and highlight the need for alternative strategies to induce high-quality T cell responses against newly arising pathogens in the elderly. [Display omitted] • SARS-CoV-2-specific T cell expansion rate indicates immune-response quality • Naive and memory pre-exposure repertoires inversely predict vaccine-response quality • Pre-existing memory T cells are excluded from high-quality vaccination responses • Impaired antigen-specific pre-exposure T cell repertoire as a hallmark of immune aging Determinants of immune-response quality to SARS-CoV-2 remain poorly defined. Saggau et al. examine spike-specific naive and memory T cells pre- and post-vaccination and track pre-existing memory T cell receptors. They define T cell parameters of high-quality vaccine responses and identify high pre-existing memory and low naive T cell contributions as predictors of low-quality responses, particularly in the elderly. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or treatment of hMPV-associated disease. Here, we used a high-throughput single-cell technology to interrogate memory B cell responses to the hMPV fusion (F) glycoprotein in young adult and elderly donors. Across all donors, the neutralizing antibody response was primarily directed to epitopes expressed on both pre- and post-fusion F conformations. However, we identified rare, highly potent broadly neutralizing antibodies that recognize pre-fusion-specific epitopes and structurally characterized an antibody that targets a site of vulnerability at the pre-fusion F trimer apex. Additionally, monotherapy with neutralizing antibodies targeting three distinct antigenic sites provided robust protection against lower respiratory tract infection in a small animal model. This study provides promising monoclonal antibody candidates for passive immunoprophylaxis and informs the rational design of hMPV vaccine immunogens. [Display omitted] • 375 antibodies from hMPV preF-reactive MBCs characterized as full-length IgGs • Neutralizing antibodies predominately target epitopes conserved on postF conformation • Structural analysis of a rare preF-specific neutralizer defines a F trimer apex epitope • 3 potent neutralizers targeting non-overlapping epitopes protect from hMPV challenge Rappazzo et al. isolate and structurally characterize monoclonal antibodies from human metapneumovirus convalescent donors that display broad and potent neutralization and recognize distinct sites on the fusion glycoprotein. Multiple antibodies demonstrate robust prophylactic efficacy in a small animal model. The results provide a framework for the development of hMPV vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of group 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine (F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstrated that both alleles encode for human IAV bnAbs that employ structurally convergent modes of contact to the same epitope. To resolve differences in lineage expandability, we compared F54 versus L54 as substrate within humanized mice, where antibodies develop with human-like CDRH3 diversity but are restricted to single V H genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supported elicitation of heterosubtypic serum bnAbs following immunization with a stalk-only nanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cells and autoreactive stalk antibodies that were cleared from B cell memory. Moreover, human stalk antibodies also demonstrated L54-dependent autoreactivity. Therefore, IGHV1-69 polymorphism, which is skewed ethnically, gates tolerance and vaccine expandability of influenza bnAbs. [Display omitted] • Both F54 and L54 IGHV1-69 alleles encode for human bnAbs against influenza virus • Only F54 IGHV1-69 can provide a substrate for vaccine-amplifying bnAbs to high titer • L54 IGHV1-69 co-endows for poly/autoreactive B cells, which become tolerized • Immune cell checkpoint inhibitors can restore L54 IGHV1-69 antibody responses Human broadly neutralizing antibodies (bnAbs) against the influenza virus preferentially use F54 IGHV1-69 as opposed to the L54 allele of this antibody V H gene. Sangesland et al. show that although both alleles encode for affinity to the same target, L54 IGHV1-69 also imparts autoreactivity, dampening vaccine expandability in a humanized mouse model. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen-independent manner and then undergo cell death. Recently, however, NK cells have been shown to possess traits of adaptive immunity and can acquire immunological memory in a manner similar to that of T and B cells. In this review, we discuss evidence of NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes. [ABSTRACT FROM AUTHOR]

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαβ repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαβ motifs in unvaccinated seroconverted children after their first virus encounter. [Display omitted] • SARS-CoV-2-specific T cells detected ex vivo in unvaccinated seroconverted children • Comparable Spike-T cell memory responses but lower ORF1a/N-responses found in children • Reduced clonal expansions within tetramer+ T cells seen in children compared with adults • Prevalent Tscm phenotype and TCR motif occur in SARS-CoV-2-specific T cells in children Children are at lower risk of developing severe COVID-19, yet their primary and memory immune responses are understudied. Rowntree et al. define ex vivo CD8+ and CD4+ T cell responses toward SARS-CoV-2 using peptide-HLA tetramers. They find that children have comparable Spike-specific but lower ORF1a- and N-specific memory T cell magnitude with less clonal expansion in comparison with adults. [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]

Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19. [Display omitted] • Vaccination of seropositive people elicits robust recall of spike-specific immunity • Immune recall following breakthrough infection is variable in timing and magnitude • Antibody recall during Delta breakthrough infection coincides with viral clearance • Omicron breakthrough infection elicits less extensive immune recall compared with Delta Koutsakos et al. analyzed the recall of spike-specific immunity following vaccination of seropositive individuals and breakthrough infections in vaccinated individuals. Compared with recall following vaccination, recall during breakthrough infections is delayed and variable in magnitude. The recall of neutralizing antibodies temporally correlated with control of Delta breakthrough infection viral load, while Omicron breakthrough elicited less extensive immune recall versus Delta. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection or vaccination produces neutralizing antibody responses that contribute to better clinical outcomes. The receptor-binding domain (RBD) and the N-terminal domain (NTD) of the spike trimer (S) constitute the two major neutralizing targets for antibodies. Here, we use NTD-specific probes to capture anti-NTD memory B cells in a longitudinal cohort of infected individuals, some of whom were vaccinated. We found 6 complementation groups of neutralizing antibodies. 58% targeted epitopes outside the NTD supersite, 58% neutralized either Gamma or Omicron, and 14% were broad neutralizers that also neutralized Omicron. Structural characterization revealed that broadly active antibodies targeted three epitopes outside the NTD supersite including a class that recognized both the NTD and SD2 domain. Rapid recruitment of memory B cells producing these antibodies into the plasma cell compartment upon re-infection likely contributes to the relatively benign course of subsequent infections with SARS-CoV-2 variants, including Omicron. [Display omitted] • Vaccination boosts anti-NTD responses against Omicron in convalescent individuals • Natural SARS-CoV-2 infection induces variant-reactive memory B cell responses to NTD • Anti-NTD neutralizing antibodies form 6 complementation groups • Structures of anti-NTD broad neutralizing antibodies reveal epitopes outside supersite Most neutralizing antibodies to SARS-CoV-2 NTD characterized to date bind a single supersite, but these antibodies were obtained by methods that were not NTD-specific. Wang et al. analyzed SARS-CoV-2 NTD-specific memory B cell responses in a longitudinal cohort of infected individuals, some of whom were vaccinated. Structural analysis revealed neutralizing epitopes conserved among variants of concern outside the NTD supersite. [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]

Summary Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4 + T cells are important for the formation of functional lung-resident CD8 + T cells after influenza virus infection. In the absence of CD4 + T cells, CD8 + T cells displayed reduced expression of CD103 ( Itgae ), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8 + T cells to the lung airways upon heterosubtypic challenge. CD4 + T cell-derived interferon-γ was necessary for generating lung-resident CD103 + CD8 + Trm cells. Furthermore, expression of the transcription factor T-bet was increased in “unhelped” lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4 + T cell help. Thus, CD4 + T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103 + CD8 + Trm cells in the lung airways following respiratory infection. [ABSTRACT FROM AUTHOR]

Resident memory B (BRM) cells develop and persist in the lungs of influenza-infected mice and humans; however, their contribution to recall responses has not been defined. Here, we used two-photon microscopy to visualize BRM cells within the lungs of influenza -virus immune and reinfected mice. Prior to re-exposure, BRM cells were sparsely scattered throughout the tissue, displaying limited motility. Within 24 h of rechallenge, these cells increased their migratory capacity, localized to infected sites, and subsequently differentiated into plasma cells. Alveolar macrophages mediated this process, in part by inducing expression of chemokines CXCL9 and CXCL10 from infiltrating inflammatory cells. This led to the recruitment of chemokine receptor CXCR3-expressing BRM cells to infected regions and increased local antibody concentrations. Our study uncovers spatiotemporal mechanisms that regulate lung BRM cell reactivation and demonstrates their capacity to rapidly deliver antibodies in a highly localized manner to sites of viral replication. [Display omitted] • Lung BRM cells localize to the alveoli and display confined probing behavior • Upon rechallenge, BRM cells increase their motility and accumulate in infected foci • BRM cell mobilization is followed by PC formation in sites of viral replication • Alveolar macrophages orchestrate this process via induction of IFNγ and CXCR3 ligands Resident memory B cells develop and persist in the lungs of influenza-infected hosts. Using 3D and live-imaging analysis of explant lung sections, MacLean et al. uncover cellular and molecular mechanisms that orchestrate the activation of these cells during secondary infection, leading to rapid delivery of antibodies in a highly localized manner directly to sites of viral replication. [ABSTRACT FROM AUTHOR]