Long-lived Bone Marrow Plasma Cells Research Articles

Majority of human circulating IgG plasmablasts stop blasting in a cell-free pro-survival culture

Following infection or vaccination, early-minted antibody secreting cells (ASC) or plasmablasts appear in circulation transiently, and a small fraction migrates to the spleen or bone marrow (BM) to mature into long-lived plasma cells (LLPC). While LLPC, by definition, are quiescent or non-dividing, the majority of blood ASC are thought to be “blasting” or proliferative. In this study, we find > 95% nascent blood ASC in culture express Ki-67 but only 6–12% incorporate BrdU after 4 h or 24 h labeling. In contrast, < 5% BM LLPC in culture are Ki-67+ with no BrdU uptake. Due to limitations of traditional flow cytometry, we utilized a novel optofluidic technology to evaluate cell division with simultaneous functional IgG secretion. We find 11% early-minted blood ASC undergo division, and none of the terminally differentiated BM LLPC (CD19−CD38hiCD138+) divide during the 7–21 days in culture. While BM LLPC undergo complete cell cycle arrest, the process of differentiation into an ASC or plasmablasts also discourages entry into S phase. Since the majority of Ki-67+ nascent blood ASC have exited cell cycle and are no longer actively “blasting”, the term “plasmablast”, which traditionally refers to an ASC that still has the capacity to divide, may probably be a misnomer.

Highly Cross-Reactive and Protective Influenza A Virus H3N2 Hemagglutinin- and Neuraminidase-Specific Human Monoclonal Antibodies.

Due to antigenic drift and shift of influenza A viruses (IAV) and the tendency to elicit predominantly strain-specific antibodies, humanity remains susceptible to new strains of seasonal IAV and is at risk from viruses with pandemic potential for which limited or no immunity may exist. The genetic drift of H3N2 IAV is specifically pronounced, resulting in two distinct clades since 2014. Here, we demonstrate that immunization with a seasonal inactivated influenza vaccine (IIV) results in increased levels of H3N2 IAV-specific serum antibodies against hemagglutinin (HA) and neuraminidase (NA). Detailed analysis of the H3N2 B cell response indicated expansion of H3N2-specific peripheral blood plasmablasts 7 days after IIV immunization which expressed monoclonal antibodies (MAbs) with broad and potent antiviral activity against many H3N2 IAV strains as well as prophylactic and therapeutic activity in mice. These H3N2-specific B cell clonal lineages persisted in CD138+ long-lived bone marrow plasma cells. These results demonstrate that IIV-induced H3N2 human MAbs can protect and treat influenza virus infection in vivo and suggest that IIV can induce a subset of IAV H3N2-specific B cells with broad protective potential, a feature that warrants further study for universal influenza vaccine development. IMPORTANCE Influenza A virus (IAV) infections continue to cause substantial morbidity and mortality despite the availability of seasonal vaccines. The extensive genetic variability in seasonal and potentially pandemic influenza strains necessitates new vaccine strategies that can induce universal protection by focusing the immune response on generating protective antibodies against conserved targets within the influenza virus hemagglutinin and neuraminidase proteins. We have demonstrated that seasonal immunization with inactivated influenza vaccine (IIV) stimulates H3N2-specific monoclonal antibodies in humans that are broad and potent in their neutralization of virus in vitro. These antibodies also provide protection from H3N2 IAV in a mouse model of infection. Furthermore, they persist in the bone marrow, where they are expressed by long-lived antibody-producing plasma cells. This significantly demonstrates that seasonal IIV can induce a subset of H3N2-specific B cells with broad protective potential, a process that if further studied and enhanced could aid in the development of a universal influenza vaccine.

COVID-19 and plasma cells: Is there long-lived protection?

SummaryInfection with SARS‐CoV‐2, the etiology of the ongoing COVID‐19 pandemic, has resulted in over 450 million cases with more than 6 million deaths worldwide, causing global disruptions since early 2020. Memory B cells and durable antibody protection from long‐lived plasma cells (LLPC) are the mainstay of most effective vaccines. However, ending the pandemic has been hampered by the lack of long‐lived immunity after infection or vaccination. Although immunizations offer protection from severe disease and hospitalization, breakthrough infections still occur, most likely due to new mutant viruses and the overall decline of neutralizing antibodies after 6 months. Here, we review the current knowledge of B cells, from extrafollicular to memory populations, with a focus on distinct plasma cell subsets, such as early‐minted blood antibody‐secreting cells and the bone marrow LLPC, and how these humoral compartments contribute to protection after SARS‐CoV‐2 infection and immunization.

Modulating Immunoglobulin Secretion of a Single Human Plasma Cell by Glycolysis Inhibition

Abstract Early-minted antibody-secreting cells (ASC) undergo further maturation to become long-lived plasma cells (LLPC) in the bone marrow (BM) microniche to afford life-long humoral protection. As terminally-differentiated cells, ASC are thought to be antibody factories that secrete immunoglobulins (Ig) constitutively. This model suggests that Ig secretion is linked with survival and loss of Ig secretion is associated with apoptosis. Here, we show that the Ig secretory function of human ASC is inhibited after treatment with an GAPDH inhibitor as measured by IgG Elispot assays and by direct visualization of IgG secretion from a single ASC. Although Ig secretion ceases quickly with the initial treatment, ASC promptly recover secretory function upon removal of the inhibitor. The modulation of Ig secretory function was directly visualized in both human early-minted blood ASC and BM LLPC by single-cell analysis using an optofluidic technology. Thus, we conclude that ASC Ig secretion is not constitutive but a dynamic process which can be modulated by metabolic processes such as glycolysis. Supported by NIH/NIAID 1R01AI121252, 1P01AI125180, U01AI141993, U54CA260563, U19AI110483, T32AI070081 and the Bill &amp; Melinda Gates Foundation Grant INV-002351.

Splenic T-bet+ B cells exhibit stem-like features and constitutively generate antibody-secreting cells

Abstract T-bet-expressing B cells (a.k.a. Age-Associated B cells or atypical B cells) directly contribute to antiviral and autoimmune responses and thus represent a promising target for immunomodulatory therapies. T-bet+ memory B cells (MBCs) form and persist long term in the spleen as a resident subset; however, the functional role of this tissue-based population and mechanisms for its maintenance are poorly understood. Here, we use T-bet reporter and fate mapping mouse models to investigate the homeostasis and fate of T-bet+ B cell subsets. We identified an elevated turnover rate of T-bet+ MBCs, with ~1.5% of the population labeling with BrdU per day and 5–10% of T-bet+ MBCs in cell cycle (G1 or S) at any given time. T-bet+ MBCs also displayed resistance to sub-lethal irradiation. Fate mapping and adoptive transfer studies demonstrate that splenic T-bethigh B cells (Tbet++ CD11c+) spontaneously give rise to T-betlow (Tbet+ CD11c−) and ultimately a variety of effector B cell subsets, including GCB-like cells, plasma cells, and T-bet− memory-like B cells, absent exogenous challenge or stimulation. T-bet+ MBCs preferentially give rise to short-lived (CD138+ B220+) versus long-lived (CD138+ B220−) bone marrow and splenic plasma cells, and adoptively transferred T-bet+ MBCs are sufficient to generate plasma IgG2c titers in IgG2a-haptolype naïve recipients. Considering their long-term maintenance in the spleen, these findings suggest T-bet+ MBCs represent a self-renewing, stem-like pool that contribute to the maintenance of antibody titers by constitutive differentiation into antibody-secreting cells.

A homologous or variant booster vaccine after Ad26.COV2.S immunization enhances SARS-CoV-2-specific immune responses in rhesus macaques.

Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in 20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques.

SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.

Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies1-7. Individuals who have recovered from COVID-19 have a substantially lower risk of reinfection with SARS-CoV-28-10. Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against SARS-CoV-2 may be short-lived11-13. Here we show that in convalescent individuals who had experienced mild SARS-CoV-2 infections (n=77), levels of serum anti-SARS-CoV-2 spike protein (S) antibodies declined rapidly in the first 4 months after infection and then more gradually over the following 7 months, remaining detectable at least 11 months after infection. Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy individuals with no history of SARS-CoV-2 infection. We show that S-binding BMPCs are quiescent, which suggests that they are part of a stable compartment. Consistently, circulating resting memory Bcells directed against SARS-CoV-2 S were detected in the convalescent individuals. Overall, our results indicate thatmild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans.

Limits and Applications of Genomic Analysis of Circulating Tumor DNA as a Liquid Biopsy in Asymptomatic Forms of Multiple Myeloma.

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B Cell Competition for Restricted T Cell Help Suppresses Rare-Epitope Responses

SUMMARYThe immune system responds preferentially to particular antigenic-epitopes contained within complex immunogens, such as proteins or microbes. This poorly understood phenomenon, termed ‘‘immunodominance,’’ remains an obstacle to achieving polyvalent immune responses against multiple anti-genic-epitopes through vaccination. We observed profound suppression in the hapten-specific antibody response in mice immunized with hapten-protein conjugate, mixed with an excess of protein, relative to that in mice immunized with hapten-protein alone. The suppression was robust (100-fold and 10-fold with a 10- or 2-fold excess of protein, respectively), stable over a 6-log range in antigen dose, observed within 10 days of vaccination, and resistant to boosting and adjuvants. Furthermore, there were reduced frequencies of antigen-specific germinal-center B cells and long-lived bone-marrow plasma cells. The mechanism of this ‘‘antigen-competition’’ was mediated largely by early access to T-helper cells. These results offer mechanistic in-sights into B cell competition during an immune response and suggest vaccination strategies against HIV, influenza, and dengue.

Improved Immune Responses in Young and Aged Mice with Adjuvanted Vaccines against H1N1 Influenza Infection.

Elderly people are at high risk for influenza-related morbidity and mortality due to progressive immunosenescence. While toll-like receptor (TLR) agonist containing adjuvants, and other adjuvants, have been shown to enhance influenza vaccine-induced protective responses, the mechanisms underlying how these adjuvanted vaccines could benefit the elderly remain elusive. Here, we show that a split H1N1 influenza vaccine (sH1N1) combined with a TLR4 agonist, glucopyranosyl lipid adjuvant formulated in a stable oil-in-water emulsion (GLA-SE), boosts IgG2c:IgG1 ratios, enhances hemagglutination inhibition (HAI) titers, and increases protection in aged mice. We find that all adjuvanted sH1N1 vaccines tested were able to protect both young and aged mice from lethal A/H1N1/California/4/2009 virus challenge after two immunizations compared to vaccine alone. We show that GLA-SE combined with sH1N1, however, also provides enhanced protection from morbidity in aged mice given one immunization (based on change in weight percentage). While the GLA-SE-adjuvanted sH1N1 vaccine promotes the generation of cytokine-producing T helper 1 cells, germinal center B cells, and long-lived bone marrow plasma cells in young mice, these responses were muted in aged mice. Differential in vitro responses, dependent on age, were also observed from mouse-derived bone marrow-derived dendritic cells and lung homogenates following stimulation with adjuvants, including GLA-SE. Besides enhanced HAI titers, additional protective factors elicited with sH1N1 + GLA-SE in young mice were observed, including (a) rapid reduction of viral titers in the lung, (b) prevention of excessive lung inflammation, and (c) homeostatic maintenance of alveolar macrophages (AMs) following H1N1 infection. Collectively, our results provide insight into mechanisms of adjuvant-mediated immune protection in the young and elderly.

A boosting skin vaccination with dissolving microneedle patch encapsulating M2e vaccine broadens the protective efficacy of conventional influenza vaccines

The biodegradable microneedle patch (MNP) is a novel technology for vaccine delivery that could improve the immunogenicity of vaccines. To broaden the protective efficiency of conventional influenza vaccines, a new 4M2e-tFliC fusion protein construct containing M2e sequences from different subtypes was generated. Purified fusion protein was encapsulate into MNPs with a biocompatible polymer for use as a boosting vaccine. The results demonstrated that mice receiving a conventional inactivated vaccine followed by a skin-applied dissolving 4M2e-tFliC MNP boost could better maintain the humoral antibody response than that by the conventional vaccine-prime alone. Compared with an intramuscular injection boost, mice receiving the MNP boost showed significantly enhanced cellular immune responses, hemagglutination-inhibition (HAI) titers, and neutralization titers. Increased frequency of antigen-specific plasma cells and long-lived bone marrow plasma cells was detected in the MNP boosted group as well, indicating that skin vaccination with 4M2e-tFliC facilitated a long-term antibody-mediated immunity. The 4M2e-tFliC MNP-boosted group also possessed enhanced protection against high lethal dose challenges against homologous A/PR/8/34 and A/Aichi/2/68 viruses and protection for a majority of immunized mice against a heterologous A/California/07/2009 H1N1 virus. High levels of M2e specific immune responses were observed in the 4M2e-tFliC MNP-boosted group as well. These results demonstrate that a skin-applied 4M2e-tFliC MNP boosting immunization to seasonal vaccine recipients may be a rapid approach for increasing the protective efficacy of seasonal vaccines in response to a significant drift seen in circulating viruses. The results also provide a new perspective for future exploration of universal influenza vaccines.

MTOR has distinct functions in generating versus sustaining humoral immunity.

Little is known about the role of mTOR signaling in plasma cell differentiation and function. Furthermore, for reasons not understood, mTOR inhibition reverses antibody-associated disease in a murine model of systemic lupus erythematosus. Here, we have demonstrated that induced B lineage-specific deletion of the gene encoding RAPTOR, an essential signaling adaptor for rapamycin-sensitive mTOR complex 1 (mTORC1), abrogated the generation of antibody-secreting plasma cells in mice. Acute treatment with rapamycin recapitulated the effects of RAPTOR deficiency, and both strategies led to the ablation of newly formed plasma cells in the spleen and bone marrow while also obliterating preexisting germinal centers. Surprisingly, although perturbing mTOR activity caused a profound decline in serum antibodies that were specific for exogenous antigen or DNA, frequencies of long-lived bone marrow plasma cells were unaffected. Instead, mTORC1 inhibition led to decreased expression of immunoglobulin-binding protein (BiP) and other factors needed for robust protein synthesis. Consequently, blockade of antibody synthesis was rapidly reversed after termination of rapamycin treatment. We conclude that mTOR signaling plays critical but diverse roles in early and late phases of antibody responses and plasma cell differentiation.

Generation of Long-Lived Bone Marrow Plasma Cells Secreting Antibodies Specific for the HIV-1 gp41 Membrane-Proximal External Region in the Absence of Polyreactivity.

ABSTRACTAn effective preventive vaccine is highly sought after in order to stem the current HIV-1 pandemic. Both conservation of contiguous gp41 membrane-proximal external region (MPER) amino acid sequences across HIV-1 clades and the ability of anti-MPER broadly neutralizing antibodies (BNAbs) to block viral hemifusion/fusion establish the MPER as a prime vaccination target. In earlier studies, we described the development of an MPER vaccine formulation that takes advantage of liposomes to array the MPER on a lipid bilayer surface, paralleling its native configuration on the virus membrane while also incorporating molecular adjuvant and CD4 T cell epitope cargo. Here we demonstrate that several immunizations with MPER/liposomes induce high levels of bone marrow long-lived plasma cell (LLPC) antibody production. Single-cell immunoglobulin gene retrieval analysis shows that these plasma cells are derived from a germ line repertoire of B cells with a diverse representation of immunoglobulin genes, exhibiting antigen-driven positive selection. Characterization of LLPC recombinant monoclonal antibodies (rMAbs) indicates that antigen recognition is achieved through convergence on a common epitopic focus by utilizing various complementarity-determining region H3 (CDRH3) lengths. Importantly, the vast majority of rMAbs produced from these cells lack polyreactivity yet manifest antigen specificity in the context of lipids, shaping MPER-specific paratopes through selective pressure. Taken together, these findings demonstrate that the MPER is a vaccine target with minimal risk of generating off-target autoimmunity.IMPORTANCE A useful vaccine must generate desired long-term, antigen-specific antibody responses devoid of polyreactivity or autoreactivity. The common polyreactive features of some HIV-1 BNAbs have raised concern about elicitation of anti-MPER antibodies. Utilizing single-LLPC repertoire analysis and biophysical characterization of anti-MPER rMAbs, we show that their fine specificities require a structural fitness of the antibody combining site involving heavy and light chain variable domains shaped by somatic hypermutation and affinity maturation of B cells in the germinal center. Perhaps more importantly, our results demonstrate that the majority of MPER-specific antibodies are not inherently polyspecific and/or autoreactive, suggesting that polyreactivity of MPER-specific antibodies is separable from their antigen specificity.

Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab

Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long-lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen.

Lasting antibody responses are mediated by a combination of newly formed and established bone marrow plasma cells drawn from clonally distinct precursors.

Current models hold that serum Ab titers are maintained chiefly by long-lived bone marrow (BM) plasma cells (PCs). In this study, we characterize the role of subpopulations of BM PCs in long-term humoral responses to T cell-dependent Ag. Surprisingly, our results indicate that 40-50% of BM PCs are recently formed cells, defined, in part, by rapid steady-state turnover kinetics and secretion of low-affinity IgM Abs. Further, for months after immunization with a hapten-protein conjugate, newly formed Ag-induced, IgM-secreting BM PCs were detected in parallel with longer-lived IgG-secreting cells, suggesting ongoing and parallel input to the BM PC pool from two distinct pools of activated B cells. Consistent with this interpretation, IgM and IgG Abs secreted by cells within distinct PC subsets exhibited distinct L chain usage. We conclude that long-term Ab responses are maintained by a dynamic BM PC pool composed of both recently formed and long-lived PCs drawn from clonally disparate precursors.

Long-lived bone marrow plasma cells are inhibited by protein A in Staphylococcus aureus infection. (VAC6P.955)

Abstract Long-lived plasma cells are now recognized as major contributors to protection against bacterial infection through their constitutive secretion of antibody. Staphylococcus aureus is a growing concern due to expansion of antibiotic resistance and causes recurring infections without inducing long-lived immunity. Little is known about the nature and longevity of the adaptive response to S. aureus. Protein A on the surface of S. aureus promotes virulence and inflammation which can alter B cell function and hinder long-lived plasma cell development. Although similar B cell responses were induced by WT and protein A-deficient infection and secondary challenge, long-term antigen-specific antibody levels waned after challenge with WT S. aureus, but were maintained after challenge with the protein A-deficient mutant. This suggests that long-lived B cell immunity is disrupted by protein A. We developed an ELISpot assay to detect S. aureus-specific antibody secreting cells and found that they accumulated in the bone marrow niche after protein A-deficient, but not WT challenge. The absence of bone marrow plasma cells after WT challenge was not a result of defects in germinal center or memory B cell formation. Our work indicates that protein A interferes with migration and/or survival of long-lived bone marrow plasma cells after S. aureus infection. It also provides insight into the requirements for successful development of long-lived immunity to bacterial pathogens.

Metabolic strategies used by long-lived bone marrow plasma cells (P1474)

Abstract Maintaining effective humoral immunity is an important aspect of healthy aging and the goal of most vaccines. Evidence from multiple laboratories agrees that long-lived humoral immunity derives from long-lived plasma cells (LLPC) that reside in the bone marrow. Because serum antibodies have a relatively short half-life and must be constantly produced, an urgent need is a clearer understanding of how LLPC maintain secretion of protective antibodies for years or a lifetime. PC secrete an estimated 1000 molecules of antibodies/sec, and some investigators make a compelling argument that the only recourse for a PC is a short lifespan, limited by oxidative and proteosomal stress. Our work begins to address how these important cells survive the extreme metabolic demands of constant antibodies secretion that is essential to lasting, protective immunity. We identified PC using the fluorescent probe ER Tracker - as highly-secretory cells, PC have large amounts of rough ER. In parallel, we stained cells with a reduced MitoTracker probe that fluoresces upon oxidation in respiring mitochondria. Our data show that ER Tracker-hi cells were found in both MitoTracker-hi and -lo populations, suggesting PC may use different metabolic strategies: aerobic respiration and glycolysis. Further studies will assess what governs each metabolic strategy, providing a deeper understanding of the cellular metabolic phenotype of long-lived plasma cells.

Plasma cells require autophagy for sustainable immunoglobulin production

The role of autophagy in plasma cells is unknown. Here we found notable autophagic activity in both differentiating and long-lived plasma cells and investigated its function through the use of mice with conditional deficiency in the essential autophagic molecule Atg5 in B cells. Atg5(-/-) differentiating plasma cells had a larger endoplasmic reticulum (ER) and more ER stress signaling than did their wild-type counterparts, which led to higher expression of the transcriptional repressor Blimp-1 and immunoglobulins and more antibody secretion. The enhanced immunoglobulin synthesis was associated with less intracellular ATP and more death of mutant plasma cells, which identified an unsuspected autophagy-dependent cytoprotective trade-off between immunoglobulin synthesis and viability. In vivo, mice with conditional deficiency in Atg5 in B cells had defective antibody responses, complete selection in the bone marrow for plasma cells that escaped Atg5 deletion and fewer antigen-specific long-lived bone marrow plasma cells than did wild-type mice, despite having normal germinal center responses. Thus, autophagy is specifically required for plasma cell homeostasis and long-lived humoral immunity.

A Replicative Self-Renewal Model for Long-Lived Plasma Cells: Questioning Irreversible Cell Cycle Exit

Plasma cells are heterogenous in terms of their origins, secretory products, and lifespan. A current paradigm is that cell cycle exit in plasma cell differentiation is irreversible, following a pattern familiar in short-lived effector populations in other hemopoietic lineages. This paradigm no doubt holds true for many plasma cells whose lifespan can be measured in days following the completion of differentiation. Whether this holds true for long-lived bone marrow plasma cells that are potentially maintained for the lifespan of the organism is less apparent. Added to this the mechanisms that establish and maintain cell cycle quiescence in plasma cells are incompletely defined. Gene expression profiling indicates that in the transition of human plasmablasts to long-lived plasma cells a range of cell cycle regulators are induced in a pattern that suggests a quiescence program with potential for cell cycle re-entry. Here a model of relative quiescence with the potential for replicative self-renewal amongst long-lived plasma cells is explored. The implications of such a mechanism would be diverse, and the argument is made here that current evidence is not sufficiently strong that the possibility should be disregarded.

Long-Lived Bone Marrow Plasma Cells Are Induced Early in Response to T Cell-Independent or T Cell-Dependent Antigens

The signals required to generate long-lived plasma cells remain unresolved. One widely cited model posits that long-lived plasma cells derive from germinal centers (GCs) in response to T cell-dependent (TD) Ags. Thus, T cell-independent (TI) Ags, which fail to sustain GCs, are considered ineffective at generating long-lived plasma cells. However, we show that long-lived hapten-specific plasma cells are readily induced without formation of GCs. Long-lived plasma cells developed in T cell-deficient mice after a single immunization with haptenated LPS, a widely used TI Ag. Long-lived plasma cells also formed in response to TD Ag when the GC response was experimentally prevented. These observations establish that long-lived plasma cells are induced in both TI and TD responses, and can arise independently of B cell maturation in GCs.