scholarly journals Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival

2012 ◽  
Vol 109 (38) ◽  
pp. 15401-15406 ◽  
Author(s):  
Xijun Ou ◽  
Shengli Xu ◽  
Kong-Peng Lam
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Antibody Responses ◽  
Cell Compartments ◽  
Follicular Helper ◽  
Inducible Costimulator ◽  
Ligand Expression

Mutations in TNFRSF13B, better known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), contribute to common variable immunodeficiency and autoimmunity in humans. How TACI regulates these two opposing conditions is unclear, however. TACI binds the cytokines BAFF and APRIL, and previous studies using gene KO mice indicated that loss of TACI affected only T-cell–independent antibody responses. Here we demonstrate that Taci−/− mice have expanded populations of T follicular helper (Tfh) and germinal center (GC) B cells in their spleens when immunized with T-cell–dependent antigen. The increased numbers of Tfh and GC B cells in Taci−/− mice are largely a result of up-regulation of inducible costimulator (ICOS) ligand on TACI-deficient B cells, given that ablation of one copy of the Icosl allele restores normal levels of Tfh and GC B cells in Taci−/− mice. Interestingly, despite the presence of increased Tfh and antigen-specific B cells, immunized Taci−/− mice demonstrate defective antigen-specific antibody responses resulting from significantly reduced numbers of antibody-secreting cells (ASCs). This effect is attributed to the failure to down-regulate the proapoptotic molecule BIM in Taci−/− plasma cells. Ablation of BIM could rescue ASC formation in Taci−/− mice, suggesting that TACI is more important for the survival of plasma cells than for the differentiation of these cells. Thus, our data reveal dual roles for TACI in B-cell terminal differentiation. On one hand, TACI modulates ICOS ligand expression and thereby limits the size of Tfh and GC B-cell compartments and prevents autoimmunity. On the other hand, it regulates the survival of ASCs and plays an important role in humoral immunity.

scholarly journals B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells

2011 ◽  
Vol 208 (7) ◽  
pp. 1377-1388 ◽  
Author(s):  
Sau K. Lee ◽  
Robert J. Rigby ◽  
Dimitra Zotos ◽  
Louis M. Tsai ◽  
Shimpei Kawamoto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Antibody Responses ◽  
B Cell Differentiation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Microbial Infections

T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell–expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6+ T cells appear at the T–B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6+ PD-1hi T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6+ T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.

T cell-intrinsic Interferon Regulatory Factor-1 expression suppresses differentiation of CD4 + T cell populations that support chronic gammaherpesvirus infection.

2021 ◽  
Author(s):  
C. N. Jondle ◽  
K. E. Johnson ◽  
W. P. Mboko ◽  
V. L. Tarakanova
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
T Cell Subsets ◽  
Viral Reservoir ◽  
B Cell Differentiation ◽  
Follicular Helper ◽  
Interferon Regulatory Factor 1 ◽  
Latent Viral Reservoir

Gammaherpesviruses are ubiquitous pathogens that establish life-long infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation. The host and viral factors that impact the gammaherpesvirus-driven germinal center response are not clearly defined. We showed that global expression of the antiviral and tumor-suppressor interferon regulatory factor 1 (IRF-1) selectively attenuates the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and restricts expansion of the latent viral reservoir. In this study we found that T cell intrinsic IRF-1 expression recapitulates some aspects of antiviral state imposed by IRF-1 during chronic MHV68 infection, including attenuation of the germinal center response and viral latency in the spleen. We also discovered that global and T cell-intrinsic IRF-1 deficiency leads to unhindered rise of IL-17A-expressing and follicular helper T cell populations, two CD4 + T cell subsets that support chronic MHV68 infection. Thus, this study unveils a novel aspect of antiviral activity of IRF-1 by demonstrating IRF-1-mediated suppression of specific CD4 + T cell subsets that support chronic gammaherpesvirus infection. Importance Gammaherpesviruses infect over 95% of the adult population, last the lifetime of the host, and are associated with multiple cancers. These viruses usurp the germinal center response to establish lifelong infection in memory B cells. This manipulation of B cell differentiation by the virus is thought to contribute to lymphomagenesis, though exactly how the virus precipitates malignant transformation in vivo is unclear. IRF-1, a host transcription factor and a known tumor suppressor, restricts the MHV68-driven germinal center response in a B cell-extrinsic manner. We found that T cell intrinsic IRF-1 expression attenuates the MHV68-driven germinal center response by restricting the CD4 + T follicular helper population. Further, our study identified IRF-1 as a novel negative regulator of IL-17-driven immune responses, highlighting the multifaceted role of IRF-1 in gammaherpesvirus infection.

scholarly journals Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kristian Assing ◽  
Christian Nielsen ◽  
Marianne Jakobsen ◽  
Charlotte B. Andersen ◽  
Kristin Skogstrand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Formation ◽  
Memory B Cells ◽  
Memory B Cell

Abstract Background Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. Case presentation We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001. Conclusions To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

scholarly journals Rapid Emergence of T Follicular Helper and Germinal Center B Cells Following Antiretroviral Therapy in Advanced HIV Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Chun-Shu Wong ◽  
Clarisa M. Buckner ◽  
Silvia Lucena Lage ◽  
Luxin Pei ◽  
Felipe L. Assis ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antiretroviral Therapy ◽  
B Cell ◽  
Germinal Center ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cd4 T Cell ◽  
Follicular Helper ◽  
Cell Counts

Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count &lt; 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.

scholarly journals Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation.

1996 ◽  
Vol 183 (5) ◽  
pp. 2303-2312 ◽  
Author(s):  
K M Toellner ◽  
A Gulbranson-Judge ◽  
D R Taylor ◽  
D M Sze ◽  
I C MacLennan
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Messenger Rna ◽  
Cell Activation ◽  
Plasma Cells ◽  
Cell Interaction ◽  
Primary Response ◽  
Antibody Responses

Immunoglobulin (Ig) class switch recombination is associated with the production and splicing of germline IgCH messenger RNA transcripts. Levels of gamma 1 transcripts in mouse spleen sections were assessed by semiquantitative analysis of reverse transcriptase polymerase chain reaction (PCR) products during primary and secondary antibody responses to chicken gamma globulin (CGG). This was correlated with the appearance of CGG-specific B cells and their growth and differentiation to plasma cells. After primary immunization with CGG, gamma 1 switch transcripts appeared after 4 d, peaked at a median of six times starting levels between 10 and 18 d after immunization, and returned to background levels before secondary immunization at 5 wk. By contrast, after secondary challenge with CGG, a sevenfold increase in transcripts occurs during the first d. The level again doubles by day 3, when it is six times that which is seen at the peak of the primary response. After day 4, there was a gradual decline over the next 2-3 wk. Within 12 h of secondary immunization, antigen-specific memory B cells appeared in the outer I zone and by 24 h entered S phase, presumably as a result of cognate interaction with primed T cells. Over the next few hours, they migrated to the edge of the red pulp, where they grew exponentially until the fourth day, when they synchronously differentiated to become plasma cells. The same pattern was seen for the migration, growth, and differentiation of virgin hapten-specific B cells when CGG-primed mice were challenged with hapten protein. The continued production of transcripts after day 3 indicates that switching also occurs in germinal centers, but in a relatively small proportion of their B cells. The impressive early production of switch transcripts during T cell-dependent antibody responses occurs in cells that are about to undergo massive clonal expansion. It is argued that Ig class switching at this time, which is associated with cognate T cell-B cell interaction in the T zone, has a major impact on the class and subclasses of Ig produced during the response.

scholarly journals B cell-intrinsic requirement for WNK1 kinase in T cell-dependent antibody responses

2021 ◽  
Author(s):  
Darryl Hayward ◽  
Lesley Vanes ◽  
Stefanie Wissmann ◽  
Sujana Sivapatham ◽  
Harald Hartweger ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Antibody Responses ◽  
B Cell Activation

AbstractMigration and adhesion play critical roles in B cells, regulating recirculation between lymphoid organs, migration within lymphoid tissue and interaction with CD4+ T cells. However, there is limited knowledge of how B cells integrate chemokine receptor and integrin signaling with B cell activation to generate efficient humoral responses. Here we show that the WNK1 kinase, a regulator of migration and adhesion, is essential in B cells for T-dependent antibody responses. We demonstrate that WNK1 transduces signals from the BCR, CXCR5 and CD40, and using intravital imaging we show that WNK1 regulates migration of naive and activated B cells, and their interactions with T cells. Unexpectedly, we show that WNK1 is required for BCR- and CD40-induced proliferation, acting through the OXSR1 and STK39 kinases, and for efficient B cell-T cell collaboration in vivo. Thus, WNK1 is critical for humoral immune responses, by regulating B cell migration, adhesion and T cell-dependent activation.SummaryThe WNK1 kinase is essential in B cells for T-dependent antibody responses because it is activated by signaling from BCR, CXCR5 and CD40 and regulates B cell migration, adhesion, T-dependent activation, and differentiation into germinal center B cells and plasma cells.

scholarly journals B cell receptor crosslinking can augment T cell help-mediated germinal center B cell selection

2018 ◽  
Author(s):  
Jackson S. Turner ◽  
Fang Ke ◽  
Irina L. Grigorova
Keyword(s):  
T Cell ◽  
B Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Receptor ◽  
Cell Selection ◽  
Antigenic Peptides ◽  
Follicular Helper ◽  
T Cell Help

AbstractSelection of germinal center (GC) B cells with B cell receptors (BCR) possessing high affinity to foreign antigen (Ag) and their differentiation into antibody-secreting long-lived plasma cells is critical for potent long-term humoral immunity. Ag-dependent engagement of GC B cell BCR triggers Ag internalization and loading of antigenic peptides on MHCII molecules for presentation to follicular helper T cells (Tfh) and acquisition of T cell help. However, whether it also provides signals that are critical or synergistic with T cell help for GC B cell selection and differentiation in vivo is not known. Here we show that T cell help is sufficient to induce GC B cell expansion and plasmablast (PB) formation in the absence of recurrent BCR engagement with Ag. Ag-mediated BCR crosslinking on the other hand is not sufficient to promote GC B cell selection, but can synergize with T cell help to enhance the GC B cell and PB responses when T cell help is limiting.

scholarly journals BATF3-dependent induction of IL-27 in B cells bridges the innate and adaptive stages of the antibody response

2020 ◽  
Author(s):  
Hui Yan ◽  
Rui Wang ◽  
Jingwei Wang ◽  
Shuai Wu ◽  
Maria Fernandez ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
Virus Infection ◽  
Antibody Response ◽  
B Cell ◽  
Antibody Responses ◽  
Follicular Helper ◽  
Antibody Secretion

AbstractB cells are exposed to innate and T cell stimuli during the antibody response, although whether and how they functionally integrate such signals are unclear. Here we have identified IL-27 as the cytokine specifically produced by murine B cells upon sequential stimulation by TLR ligands and then CD154 and IL-21, the hallmark factors of T follicular helper cells, and during the T-dependent antibody response to a conjugated hapten or virus infection. B-cell Il27p28 transcription is concomitant with increased locus accessibility and depends on newly induced BATF3 transcription factor. IL-27-producing B cells are inefficient in antibody secretion, but cooperate with IFNγ to promote proliferation, survival, class-switching and plasma cell differentiation of CD40-activated B cells, leading to optimal IgG2a and IgG1 responses. Overall, IL-27-producing B cells function as “helper” B cells that integrate the innate and adaptive stages of the antibody response.One-sentence summaryB cells integrate innate TLR and adaptive CD40 signals to induce BATF3 transcription factor for production of IL-27, which together with INFg optimizes antibody responses.

scholarly journals ZBTB38 is dispensable for hematopoiesis and antibody responses

2020 ◽  
Author(s):  
Rachel Wong ◽  
Deepta Bhattacharya
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Antibody Responses ◽  
Conditional Knockout ◽  
B Cell Differentiation ◽  
Normal Numbers ◽  
Hematopoietic Stem ◽  
Germinal Center B Cells

AbstractMembers of the broad complex, tram track, bric-a-brac and zinc finger (BTB-ZF) family of transcription factors, such as BCL-6, ZBTB20, and ZBTB32, regulate antigen-specific B cell differentiation, plasma cell longevity, and the duration of antibody production. We found that ZBTB38, a different member of the BTB-ZF family that binds methylated DNA at CpG motifs, is highly expressed by germinal center B cells and plasma cells. To define the functional role of ZBTB38 in B cell responses, we generated mice conditionally deficient in this transcription factor. Germinal center B cells lacking ZBTB38 dysregulated very few genes relative to wild-type and heterozygous littermate controls. Accordingly, mice with hematopoietic-specific deletion of Zbtb38 showed normal germinal center B cell numbers and antibody responses following immunization with hapten-protein conjugates. Memory B cells from these animals functioned normally in secondary recall responses. Despite expression of ZBTB38 in hematopoietic stem cells, progenitors and mature myeloid and lymphoid lineages were also present in normal numbers in mutant mice. These data demonstrate that ZBTB38 is dispensable for hematopoiesis and antibody responses. These conditional knockout mice may instead be useful in defining the functional importance of ZBTB38 in other cell types and contexts.

scholarly journals Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

1997 ◽  
Vol 185 (12) ◽  
pp. 2121-2131 ◽  
Author(s):  
Robbert van der Voort ◽  
Taher E.I. Taher ◽  
Robert M.J. Keehnen ◽  
Lia Smit ◽  
Martijn Groenink ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Germinal Center ◽  
Scatter Factor ◽  
Hepatocyte Growth

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

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