RESUMO
For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Memória Imunológica , Plasmócitos/imunologia , Plasmócitos/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Memória Imunológica/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Transcrição GênicaRESUMO
Maintenance of immunological self-tolerance requires lymphocytes carrying self-reactive antigen receptors to be selectively prevented from mounting destructive or inflammatory effector responses. Classically, self-tolerance is viewed in terms of the removal, editing, or silencing of B and T cells that have formed self-reactive antigen receptors during their early development. However, B cells activated by foreign antigen can enter germinal centers (GCs), where they further modify their antigen receptor by somatic hypermutation (SHM) of their immunoglobulin genes. The inevitable emergence of activated, self-reactive GC B cells presents a unique challenge to the maintenance of self-tolerance that must be rapidly countered to avoid autoantibody production. Here we discuss current knowledge of the mechanisms that enforce B cell self-tolerance, with particular focus on the control of self-reactive GC B cells. We also consider how self-reactive GC B cells can escape self-tolerance to initiate autoantibody production or instead be redeemed via SHM and used in productive antibody responses.
Assuntos
Autoimunidade , Linfócitos B/imunologia , Centro Germinativo/imunologia , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Linfócitos B/metabolismo , Centro Germinativo/metabolismo , Humanos , Tolerância Imunológica , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
We comprehensively review memory B cells (MBCs), covering the definition of MBCs and their identities and subsets, how MBCs are generated, where they are localized, how they are maintained, and how they are reactivated. Whereas naive B cells adopt multiple fates upon stimulation, MBCs are more restricted in their responses. Evolving work reveals that the MBC compartment in mice and humans consists of distinct subpopulations with differing effector functions. We discuss the various approaches to define subsets and subset-specific roles. A major theme is the need to both deliver faster effector function upon reexposure and readapt to antigenically variant pathogens while avoiding burnout, which would be the result if all MBCs generated only terminal effector function. We discuss cell-intrinsic differences in gene expression and signaling that underlie differences in function between MBCs and naive B cells and among MBC subsets and how this leads to memory responses.
Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Memória Imunológica , Vacinas/imunologia , Animais , Humanos , Imunidade Humoral , Ativação Linfocitária , Camundongos , TranscriptomaRESUMO
The membrane protein NINJ1 mediates plasma membrane rupture in pyroptosis and other lytic cell death pathways. Here, we report the cryo-EM structure of a NINJ1 oligomer segmented from NINJ1 rings. Each NINJ1 subunit comprises amphipathic (âº1, âº2) and transmembrane (TM) helices (âº3, âº4) and forms a chain of subunits, mainly by the TM helices and âº1. âº3 and âº4 are kinked, and the Gly residues are important for function. The NINJ1 oligomer possesses a concave hydrophobic side that should face the membrane and a convex hydrophilic side formed by âº1 and âº2, presumably upon activation. This structural observation suggests that NINJ1 can form membrane disks, consistent with membrane fragmentation by recombinant NINJ1. Live-cell and super-resolution imaging uncover ring-like structures on the plasma membrane that are released into the culture supernatant. Released NINJ1 encircles a membrane inside, as shown by lipid staining. Therefore, NINJ1-mediated membrane disk formation is different from gasdermin-mediated pore formation, resulting in membrane loss and plasma membrane rupture.
Assuntos
Moléculas de Adesão Celular Neuronais , Membrana Celular , Microscopia Crioeletrônica , Membrana Celular/metabolismo , Humanos , Moléculas de Adesão Celular Neuronais/metabolismo , Moléculas de Adesão Celular Neuronais/química , Animais , Camundongos , Células HEK293 , Piroptose , Modelos Moleculares , Proteínas de Membrana/metabolismo , Proteínas de Membrana/química , Proteínas de Ligação a Fosfato/metabolismoRESUMO
Germinal centers (GCs) form in lymph nodes after immunization or infection to facilitate antibody affinity maturation and memory and plasma cell (PC) development. PC differentiation is thought to involve stringent selection for GC B cells expressing the highest-affinity antigen receptors, but how this plays out during complex polyclonal responses is unclear. We combine temporal lineage tracing with antibody characterization to gain a snapshot of PCs developing during influenza infection. GCs co-mature B cell clones with antibody affinities spanning multiple orders of magnitude; however, each generates PCs with similar efficiencies, including weak binders. Within lineages, PC selection is not restricted to variants with the highest-affinity antibodies. Differentiation is commonly associated with proliferative expansion to produce "nodes" of identical PCs. Immunization-induced GCs generate fewer PCs but still of low- and high-antibody affinities. We propose that generating low-affinity antibody PCs reflects an evolutionary compromise to facilitate diverse serum antibody responses.
Assuntos
Afinidade de Anticorpos , Linfócitos B , Centro Germinativo , Plasmócitos , Formação de Anticorpos , Linfócitos B/citologia , Linfócitos B/imunologia , Linfonodos , Linhagem Celular , Humanos , Animais , Camundongos , Cricetinae , Vírus da Influenza A/imunologia , Diferenciação CelularRESUMO
ß-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-ß-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in ß-arrestin interactions with both receptors and the lipid bilayer. Unexpectedly, our results reveal that ß-arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover, they indicate that, following receptor interaction, the plasma membrane stabilizes ß-arrestin in a longer-lived, membrane-bound state, allowing it to diffuse to clathrin-coated pits separately from the activating receptor. These results expand our current understanding of ß-arrestin function at the plasma membrane, revealing a critical role for ß-arrestin preassociation with the lipid bilayer in facilitating its interactions with receptors and subsequent activation.
Assuntos
Receptores Acoplados a Proteínas G , Transdução de Sinais , beta-Arrestinas , beta-Arrestinas/metabolismo , Membrana Celular/metabolismo , Clatrina/metabolismo , Endocitose , Bicamadas Lipídicas , Receptores Acoplados a Proteínas G/metabolismo , Simulação de Dinâmica MolecularRESUMO
The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.
Assuntos
Anticorpos Antineoplásicos , Neoplasias Ovarianas , Anticorpos Monoclonais , Autoanticorpos , Autoantígenos , Feminino , Humanos , Neoplasias Ovarianas/genética , Microambiente TumoralRESUMO
Every eukaryotic cell contains two distinct multisubunit protein kinase complexes that each contain a TOR (target of rapamycin) protein as the catalytic subunit. These ensembles, designated TORC1 and TORC2, serve as nutrient and stress sensors, signal integrators, and regulators of cell growth and homeostasis, but they differ in their composition, localization, and function. TORC1, activated on the cytosolic surface of the vacuole (or, in mammalian cells, on the cytosolic surface of the lysosome), promotes biosynthesis and suppresses autophagy. TORC2, located primarily at the plasma membrane (PM), maintains the proper levels and bilayer distribution of all PM components (sphingolipids, glycerophospholipids, sterols, and integral membrane proteins), which are needed for the membrane expansion that accompanies cell growth and division and for combating insults to PM integrity. This review summarizes our current understanding of the assembly, structural features, subcellular distribution, and function and regulation of TORC2, obtained largely through studies conducted with Saccharomyces cerevisiae.
RESUMO
Located at the inner leaflet of the plasma membrane (PM), phosphatidyl-inositol 4,5-bisphosphate [PI(4,5)P2] composes only 1-2 mol% of total PM lipids. With its synthesis and turnover both spatially and temporally regulated, PI(4,5)P2 recruits and interacts with hundreds of cellular proteins to support a broad spectrum of cellular functions. Several factors contribute to the versatile and dynamic distribution of PI(4,5)P2 in membranes. Physiological multivalent cations such as Ca2+ and Mg2+ can bridge between PI(4,5)P2 headgroups, forming nanoscopic PI(4,5)P2-cation clusters. The distinct lipid environment surrounding PI(4,5)P2 affects the degree of PI(4,5)P2 clustering. In addition, diverse cellular proteins interacting with PI(4,5)P2 can further regulate PI(4,5)P2 lateral distribution and accessibility. This review summarizes the current understanding of PI(4,5)P2 behavior in both cells and model membranes, with emphasis on both multivalent cation- and protein-induced PI(4,5)P2 clustering. Understanding the nature of spatially separated pools of PI(4,5)P2 is fundamental to cell biology.
Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Replicação Viral/fisiologia , Animais , Membrana Celular/metabolismo , Humanos , Micelas , Fosfatidilinositol 4,5-Difosfato/química , Proteínas Virais/metabolismoRESUMO
Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.
Assuntos
Linfócitos B/imunologia , COVID-19/imunologia , Memória Imunológica , Adulto , COVID-19/fisiopatologia , Citometria de Fluxo , Centro Germinativo/citologia , Humanos , Ativação Linfocitária , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Análise de Célula Única , Glicoproteína da Espícula de Coronavírus/químicaRESUMO
Chloroplasts are crucial players in the activation of defensive hormonal responses during plant-pathogen interactions. Here, we show that a plant virus-encoded protein re-localizes from the plasma membrane to chloroplasts upon activation of plant defense, interfering with the chloroplast-dependent anti-viral salicylic acid (SA) biosynthesis. Strikingly, we have found that plant pathogens from different kingdoms seem to have convergently evolved to target chloroplasts and impair SA-dependent defenses following an association with membranes, which relies on the co-existence of two subcellular targeting signals, an N-myristoylation site and a chloroplast transit peptide. This pattern is also present in plant proteins, at least one of which conversely activates SA defenses from the chloroplast. Taken together, our results suggest that a pathway linking plasma membrane to chloroplasts and activating defense exists in plants and that such pathway has been co-opted by plant pathogens during host-pathogen co-evolution to promote virulence through suppression of SA responses.
Assuntos
Membrana Celular/imunologia , Cloroplastos/imunologia , Doenças das Plantas/imunologia , Imunidade Vegetal/imunologia , Transdução de Sinais/imunologia , Proteínas de Arabidopsis/imunologia , Interações Hospedeiro-Patógeno/imunologia , Ácido Salicílico/imunologia , Virulência/imunologiaRESUMO
Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal immunoglobulin Gs (IgGs) and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1A and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4 Å cryo-electron microscopy (cryo-EM) structure of a neutralizing monoclonal Fab-spike complex revealed an epitope that blocks ACE2 receptor binding. Modeling based on these structures suggested different potentials for inter-spike crosslinking by IgGs on viruses, and characterized IgGs would not be affected by identified SARS-CoV-2 spike mutations. Overall, our studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3-53/VH3-66 and similarity to a SARS-CoV VH3-30 antibody, providing criteria for evaluating vaccine-elicited antibodies.
Assuntos
Anticorpos Neutralizantes/química , Betacoronavirus/química , Infecções por Coronavirus/imunologia , Fragmentos Fab das Imunoglobulinas/química , Imunoglobulina G/química , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/química , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/isolamento & purificação , Betacoronavirus/imunologia , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/terapia , Reações Cruzadas , Microscopia Crioeletrônica , Mapeamento de Epitopos , Epitopos , Humanos , Imunização Passiva , Fragmentos Fab das Imunoglobulinas/sangue , Fragmentos Fab das Imunoglobulinas/isolamento & purificação , Fragmentos Fab das Imunoglobulinas/ultraestrutura , Imunoglobulina G/sangue , Imunoglobulina G/isolamento & purificação , Imunoglobulina G/ultraestrutura , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Modelos Moleculares , Pandemias , Pneumonia Viral/sangue , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/química , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia , Soroterapia para COVID-19RESUMO
Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding was observed from the upper respiratory tract of a female immunocompromised individual with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and of genomic and subgenomic RNA up to 105 days, after initial diagnosis. The infection was not cleared after the first treatment with convalescent plasma, suggesting a limited effect on SARS-CoV-2 in the upper respiratory tract of this individual. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2 with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised individuals may shed infectious virus longer than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2-positive individuals as a proxy for shedding of infectious virus.
Assuntos
COVID-19/imunologia , Imunodeficiência de Variável Comum/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , SARS-CoV-2/isolamento & purificação , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/complicações , COVID-19/virologia , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/virologia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/virologia , Infecções Respiratórias/sangue , Infecções Respiratórias/complicações , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidadeRESUMO
B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.
Assuntos
Linfócitos B/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Memória Imunológica , Plasmócitos/imunologia , Plasmócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas/imunologiaRESUMO
Sphingomyelin and cholesterol are essential lipids that are enriched in plasma membranes of animal cells, where they interact to regulate membrane properties and many intracellular signaling processes. Despite intense study, the interaction between these lipids in membranes is not well understood. Here, structural and biochemical analyses of ostreolysin A (OlyA), a protein that binds to membranes only when they contain both sphingomyelin and cholesterol, reveal that sphingomyelin adopts two distinct conformations in membranes when cholesterol is present. One conformation, bound by OlyA, is induced by stoichiometric, exothermic interactions with cholesterol, properties that are consistent with sphingomyelin/cholesterol complexes. In its second conformation, sphingomyelin is free from cholesterol and does not bind OlyA. A point mutation abolishes OlyA's ability to discriminate between these two conformations. In cells, levels of sphingomyelin/cholesterol complexes are held constant over a wide range of plasma membrane cholesterol concentrations, enabling precise regulation of the chemical activity of cholesterol.
Assuntos
Membrana Celular/ultraestrutura , Esfingomielinas/metabolismo , Esfingomielinas/fisiologia , Animais , Linhagem Celular , Membrana Celular/metabolismo , Colesterol/metabolismo , Colesterol/fisiologia , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/ultraestrutura , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/ultraestrutura , Humanos , Microdomínios da Membrana/metabolismo , Conformação MolecularRESUMO
Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.
Assuntos
Imunoglobulina A/metabolismo , Interleucina-10/metabolismo , Intestinos/imunologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Humanos , Imunoglobulina A/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Neuroimunomodulação/imunologia , Plasmócitos/metabolismoRESUMO
Over the last several decades, an impressive array of advanced microscopic and analytical tools, such as single-particle tracking and nanoscopic fluorescence correlation spectroscopy, has been applied to characterize the lateral organization and mobility of components in the plasma membrane. Such analysis can tell researchers about the local dynamic composition and structure of membranes and is important for predicting the outcome of membrane-based reactions. However, owing to the unresolved complexity of the membrane and the structures peripheral to it, identification of the detailed molecular origin of the interactions that regulate the organization and mobility of the membrane has not proceeded quickly. This Perspective presents an overview of how cell-surface structure may give rise to the types of lateral mobility that are observed and some potentially fruitful future directions to elucidate the architecture of these structures in more molecular detail.
Assuntos
Membrana Celular/metabolismo , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/metabolismo , Membrana Celular/fisiologia , Bicamadas Lipídicas/química , Lipídeos de Membrana/metabolismo , Microdomínios da Membrana/química , Proteínas de Membrana/fisiologiaRESUMO
Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. High-affinity cells are proposed to preferentially select into this compartment, potentiating the immune response. We used single-cell RNA-seq to track the germinal center (GC) development of Ighg2A10 B cells, specific for the Plasmodium falciparum circumsporozoite protein (PfCSP). Following immunization with Plasmodium sporozoites, we identified 3 populations of cells in the GC light zone (LZ). One LZ population expressed a gene signature associated with the initiation of PC differentiation and readily formed PCs in vitro. The estimated affinity of these pre-PC B cells was indistinguishable from that of LZ cells that remained in the GC. This remained true when high- or low-avidity recombinant PfCSP proteins were used as immunogens. These findings suggest that the initiation of PC development occurs via an affinity-independent process.
Assuntos
Linfócitos B , Centro Germinativo , Plasmócitos , Diferenciação Celular , Células Precursoras de Linfócitos BRESUMO
Expression of the transcriptional regulator ZFP318 is induced in germinal center (GC)-exiting memory B cell precursors and memory B cells (MBCs). Using a conditional ZFP318 fluorescence reporter that also enables ablation of ZFP318-expressing cells, we found that ZFP318-expressing MBCs were highly enriched with GC-derived cells. Although ZFP318-expressing MBCs constituted only a minority of the antigen-specific MBC compartment, their ablation severely impaired recall responses. Deletion of Zfp318 did not alter the magnitude of primary responses but markedly reduced MBC participation in recall. CD40 ligation promoted Zfp318 expression, whereas B cell receptor (BCR) signaling was inhibitory. Enforced ZFP318 expression enhanced recall performance of MBCs that otherwise responded poorly. ZFP318-deficient MBCs expressed less mitochondrial genes, had structurally compromised mitochondria, and were susceptible to reactivation-induced cell death. The abundance of ZFP318-expressing MBCs, instead of the number of antigen-specific MBCs, correlated with the potency of prime-boost vaccination. Therefore, ZFP318 controls the MBC recallability and represents a quality checkpoint of humoral immune memory.
Assuntos
Centro Germinativo , Memória Imunológica , Células B de Memória , Mitocôndrias , Animais , Mitocôndrias/metabolismo , Mitocôndrias/imunologia , Camundongos , Memória Imunológica/genética , Memória Imunológica/imunologia , Células B de Memória/imunologia , Células B de Memória/metabolismo , Centro Germinativo/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Regulação da Expressão Gênica , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Transdução de Sinais/imunologia , Antígenos CD40/metabolismo , Antígenos CD40/genética , Antígenos CD40/imunologia , Imunidade Humoral , Transcrição Gênica , Proteínas de Membrana , Proteínas MitocondriaisRESUMO
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.