Maintenance Of Long-lived Plasma Cells Research Articles

Insights into the relationship between persistent antibody secretion and metabolic programming – A question for single-cell analysis

Vaccination aims to generate a protective and persisting antibody response. Indeed, humoral vaccine-mediated protection depends on the quality and quantity of the produced antigen-specific antibodies for its initial magnitude and the persistence of the plasma cells for its duration. Therefore, understanding the mechanisms behind the generation, selection and maintenance of long-lived plasma cells secreting protective antibodies is of fundamental importance for understanding long-term immunity, vaccine responses, therapeutical approaches for autoimmune disease and multiple myeloma. Recent studies have observed correlations between the generation, function and lifespan of plasma cells and their metabolism, with metabolism being both a main driver and primary consequence of changes in cellular behavior. This review introduces how metabolic programs influence and drive immune cell functions in general and plasma cell differentiation and longevity more specifically, summarizing the current knowledge on metabolic pathways and their influences on cellular fate. In addition, available technologies to profile metabolism and their limitations are discussed, leading to the unique and open technological challenges for further advancement of this research field.

The secret to longevity, plasma cell style.

An enduring antibody response is ultimately dependent on the generation and maintenance of long-lived plasma cells. New research describes the use of single-cell transcriptomics approaches to reveal the defining features of longevity in plasma cells.

MiR-148a controls metabolic programming and survival of mature CD19-negative plasma cells in mice.

Long-lived antibody-secreting plasma cells are essential to establish humoral memory against pathogens. While a regulatory transcription factor network has been established in plasma cell differentiation, the regulatory role of miRNAs remains enigmatic. We have recently identified miR-148a as the most abundant miRNA in primary mouse and human plasma cells. To determine whether this plasma cell signature miRNA controls the in vivo development of B cells into long-lived plasma cells, we established mice with genomic, conditional, and inducible deletions of miR-148a. The analysis of miR-148a-deficient mice revealed reduced serum Ig, decreased numbers of newly formed plasmablasts and reduced CD19-negative, CD93-positive long-lived plasma cells. Transcriptome and metabolic analysis revealed an impaired glucose uptake, a reduced oxidative phosphorylation-based energy metabolism, and an altered abundance of homing receptors CXCR3 (increase) and CXCR4 (reduction) in miR-148a-deficient plasma cells. These findings support the role of miR-148a as a positive regulator of the maintenance of long-lived plasma cells.

The BCMA:Tomato Mouse – a new reporter to characterize long-lived plasma cells

Abstract Plasma cells provide humoral protection by secreting large amounts of antibodies. The heterogeneity of the plasma cell compartment has recently been demonstrated by functional studies and subpopulation markers, but the distinct properties of long-lived plasma cells (LLPC) are still unresolved. B Cell Maturation Antigen (BCMA) has been described as an essential receptor for LLPC survival. To elucidate the mechanisms of BCMA-mediated survival we established a reporter mouse line that expresses a tdTomato fluorescent protein together with BCMA under the control of the promoter of Tnfrsf17, the gene that encodes BCMA. In this reporter model, we could demonstrate the restricted expression of Tomato and BCMA in plasma cells making this an ideal system for the identification and tracking of plasma cells. Importantly, we observed an increase in the abundance of BCMA:Tomato along with a gradual loss of CD19 expression, delineating a developmental progression from plasmablasts to mature plasma cell subsets. In contrast, plasmablasts generated in vitro display only minimal BCMA induction, confirming the independence of BCMA expression from the Blimp1 master regulator of PC differentiation. In summary, we have developed a new plasma cell-specific reporter model that, together with an inducible BCMA-KO mouse, will allow us to investigate the BCMA-dependent signals of the generation and maintenance of LLPC. This work was supported, in part, by the Deutsche Forschungsgemeinschaft (DFG) through research grants TRR130 to H.-M.J. and W.S. and GRK1660 to H.-M.J.

Chinese‐German Cooperation Group Tumor Immunology: Another inspiring Meeting in Deidesheim

Chinese‐German Cooperation Group Tumor Immunology: Another inspiring Meeting in Deidesheim

Programming plasma cell survival

![Figure][1] Insight from Ulf Klein In this issue, two independent groups show that the transcription factor ZBTB20 is required for the maintenance of long-lived plasma cells following immunization with the commonly used adjuvant, alum. Intriguingly, one group found that ZBTB20 was

SAT0168 Targeting of long-lived plasma cells in autoimmune NZB/W mice

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the generation of pathogenic antibodies directed against a variety of autoantigens. We have previously shown that long-lived plasma cells...

Memory B cells are required to maintain long-lived plasma cells in mice following viral infections (132.16)

Abstract Antibody responses have been found to last for life following lymphocytic choriomeningitis virus (LCMV) infection in mice and have been estimated to have a half-life of up to 200 years for some pathogens in humans. These antibodies are produced by long-lived plasma cells which have been shown to have a half-life of at least 138 days in mice. However, the role of memory B cells in the maintenance of plasma cell numbers remains unclear. We have been attempting to define this role by infecting hCD20 transgenic mice with viral pathogens, treating them with rituximab (an anti-CD20 antibody), and then following the antibody levels in these mice. Rituximab treatment of hCD20 mice selectively depletes naive and memory B cells while leaving plasma cells untouched. During long-term treatment of LCMV immune mice, there is a slow, steady decline of antibody levels and a decrease in the number of LCMV-specific antibody secreting cells in the spleen and bone marrow. This decrease in antibody levels was also observed with influenza and vesicular stomatitis virus (VSV) infected mice and correlates with decreased hemagglutination inhibition titers in influenza infections and decreased neutralization titers in VSV infections. These results suggest a critical role for memory B cells in the maintenance of long-lived plasma cells following viral infections. This work was supported by NIH grant AI30048.

Regulation and Functions of Blimp-1 in T and B Lymphocytes

B lymphocyte-induced maturation protein-1 (Blimp-1), discovered 16 years ago as a transcriptional repressor of the IFNbeta promoter, plays fundamentally important roles in many cell lineages and in early development. This review focuses on Blimp-1 in lymphocytes. In the B cell lineage, Blimp-1 is required for development of immunoglobulin-secreting cells and for maintenance of long-lived plasma cells (LLPCs). Direct targets of Blimp-1 and the transcriptional cascades Blimp-1 initiates to trigger plasmacytic differentiation are described. Blimp-1 also affects the homeostasis and function of CD4(+), CD8(+), and regulatory CD4(+) T cells, and Blimp-1 levels are highest in antigen-experienced T cells. Blimp-1 attenuates T cell proliferation and survival and modulates differentiation. Roles for Blimp-1 in Th1/Th2 specification, regulatory T cell function, and CD8 differentiation and function are under investigation. Signals that induce Blimp-1 in B cells include Toll-like receptor ligands and cytokines; in T cells, T cell receptors and cytokines induce Blimp-1. In spite of some commonalities, different targets and regulators of Blimp-1 in B and T cells suggest intriguing evolutionary divergence of this regulatory machinery.

Maintenance of Long-Lived Plasma Cells and Serological Memory Despite Mature and Memory B Cell Depletion during CD20 Immunotherapy in Mice

CD20 mAb-mediated B cell depletion is an effective treatment for B cell malignancies and some autoimmune diseases. However, the full effects of B cell depletion on natural, primary, and secondary Ab responses and the maintenance of Ag-specific serum Ig levels are largely unknown. The relationship between memory B cells, long-lived plasma cells, and long-lived humoral immunity also remains controversial. To address the roles of B cell subsets in the longevity of humoral responses, mature B cells were depleted in mice using CD20 mAb. Peritoneal B cell depletion reduced natural and Ag-induced IgM responses. Otherwise, CD20+ B cell depletion prevented humoral immune responses and class switching and depleted existing and adoptively transferred B cell memory. Nonetheless, B cell depletion did not affect serum Ig levels, Ag-specific Ab titers, or bone marrow Ab-secreting plasma cell numbers. Coblockade of LFA-1 and VLA-4 adhesion molecules temporarily depleted long-lived plasma cells from the bone marrow. CD20+ B cell depletion plus LFA-1/VLA-4 mAb treatment significantly prolonged Ag-specific plasma cell depletion from the bone marrow, with a significant decrease in Ag-specific serum IgG. Collectively, these results support previous claims that bone marrow plasma cells are intrinsically long-lived. Furthermore, these studies now demonstrate that mature and memory B cells are not required for maintaining bone marrow plasma cell numbers, but are required for repopulation of plasma cell-deficient bone marrow. Thereby, depleting mature and memory B cells does not have a dramatic negative effect on preexisting Ab levels.

Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow

Long-lived plasma cells, residing primarily in the bone marrow, continuously secrete antibody and provide an important component of humoral memory. However, when such cells secrete autoantibodies or become transformed, they can be pathogenic. We have shown recently that the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp-1) is required for the formation of plasma cells. To determine what role Blimp-1 might play in maintenance of plasma cells, we generated mice in which the gene encoding Blimp-1 could be deleted in an inducible manner. Deletion of Blimp-1 either in vitro or in vivo leads to loss of previously formed B220LOCD138HI plasma cells. Using BrdU incorporation, we confirmed that Blimp-1 is required for the maintenance of nondividing, long-lived plasma cells in the bone marrow. Blimp-1 is also required for long-term maintenance of antigen-specific immunoglobulin in serum. Thus Blimp-1 is required not only for the formation but also for the maintenance of long-lived plasma cells. This finding provides the possibility of new drug design strategies for autoimmunity and multiple myeloma focused on blocking Blimp-1 expression or activity.

Regulatory events in early and late B-cell differentiation

We are studying transcriptional control of critical developmental decision points in B lymphocytes. Commitment to the B-lymphocyte lineage is dependent on the transcriptional regulator Pax5 and committed B lymphocytes represent the first developmental stage when V H-to-DJ recombination occurs in the immunoglobulin (Ig) heavy chain locus. We summarize our recent studies showing that methylation of histone H3 lysine 9, a heterochromatic chromatin modification, is present in the Ig V H region in hematopoietic progenitors and in non-B lineage hematopoietic cells. Pax5 is both necessary and sufficient to remove this heterochromatic mark in B cells. Using genetically altered mice, we have shown that terminal differentiation of B cells to memory and Ig-secreting plasma cells depends on the transcriptional repressor Blimp-1. Recent studies demonstrating a requirement for Blimp-1 in the formation of pre-plasma memory B cells, Ig-secreting plasma cells as well as preliminary data suggesting a requirement for Blimp-1 in the maintenance of long-lived plasma cells are summarized. We also summarize our recent studies on the regulation of Blimp-1, showing direct repression by Bcl-6 and providing evidence for activation by NF-κB following toll-like receptor signaling.