scholarly journals Atypical B cells upregulate co-stimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

2021 ◽  
Author(s):  
Christine S. Hopp ◽  
Jeff Skinner ◽  
Sarah L. Anzick ◽  
Christopher M. Tipton ◽  
Mary E. Peterson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Somatic Hypermutation ◽  
Acute Infection ◽  
Cell Receptor ◽  
Tfh Cells ◽  
Influenza Hemagglutinin ◽  
Follicular Helper ◽  
T Cell Help

ABSTRACTSeveral infectious and autoimmune diseases are associated with an expansion of CD21-CD27- atypical B cells (atBCs). The function of atBCs remains unclear and few studies have investigated the biology of pathogen-specific atBCs during acute infection. Here, we performed longitudinal RNA-sequencing and flow cytometry analyses of Plasmodium falciparum (Pf)-specific B cells before and shortly after febrile malaria, with simultaneous analysis of influenza hemagglutinin (HA)-specific B cells as a comparator. B cell receptor-sequencing showed that Pf-specific atBCs, activated B cells (actBCs) and classical memory B cells share clonality and have comparable somatic hypermutation. In response to malaria, Pf-specific atBCs and actBCs expanded and upregulated molecules that mediate B-T cell interactions, suggesting that atBCs respond to T follicular helper (Tfh) cells. Indeed, in the presence of Tfh cells and Staphylococcal enterotoxin B, atBCs of malaria-exposed individuals differentiated into CD38+ antibody-secreting cells in vitro, suggesting that atBCs may actively contribute to humoral immunity to infectious pathogens.One Sentence SummaryThis study shows that atypical B cells actively respond to acute malaria and have the capacity to produce antibodies with T cell help.

scholarly journals Outer Periarteriolar Lymphoid Sheath Arrest and Subsequent Differentiation of Both Naive and Tolerant Immunoglobulin Transgenic B Cells Is Determined by B Cell Receptor Occupancy

1997 ◽  
Vol 186 (5) ◽  
pp. 631-643 ◽  
Author(s):  
Matthew C. Cook ◽  
Antony Basten ◽  
Barbara Fazekas de St. Groth
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Receptor Occupancy ◽  
Cell Receptor ◽  
Antigen Concentration ◽  
Identical Manner ◽  
T Cell Help ◽  
Self Antigen

T-dependent B cell responses in the spleen are initiated in the outer periarteriolar lymphoid sheath (PALS) and culminate in the generation of proliferative foci and germinal center reactions. By pulsing anti–hen egg lysozyme (HEL) immunoglobulin transgenic (IgTg) B cells with various concentrations of HEL in vitro before adoptive transfer into normal recipients, it was shown that a critical number of B cell receptors (BCRs) must be ligated for B cells to undergo arrest in the outer PALS. T cell help was manipulated independently of the BCR stimulus by incubating B cells expressing the appropriate major histocompatibility complex class II antigen with a peptide recognized by CD4+ TCR Tg T cells. B cells which either failed to arrest in the outer PALS due to a subthreshold BCR stimulus, or arrested only transiently due to the brevity of the BCR stimulus, underwent an abortive response within the follicles when provided with T cell help. In contrast, naive B cells stimulated by a sustained, suprathreshold concentration of either foreign or self-antigen and given T cell help, proliferated in the outer PALS and then differentiated. Outer PALS arrest was not influenced by the nature of the B cells occupying the follicle, but appeared to be determined solely by the magnitude of BCR stimulation. Thus antigen-pulsed B cells arrested in the outer PALS in an identical manner irrespective of whether the follicles comprised a population of normal B cells with multiple specificities, a monoclonal naive population, or a monoclonal population of tolerant B cells. In addition, tolerant B cells were found to relocate from the follicles to the outer PALS of HEL/anti-HEL double Tg mice in which the concentration of soluble self-antigen had been increased by zinc feeding. Similarly, when anti-HEL Tg mice were crossed with a second HEL Tg strain expressing a higher concentration of soluble HEL, the tolerant anti-HEL Tg B cells were located constitutively in the outer PALS. Thus, subtle variations in antigen concentration resulted in dramatic changes in positioning of B cells within the spleen. A series of mixed bone marrow chimeras in which the effective antigen concentration was inversely related to the number of self-reactive B cells due to absorption of antigen by transgene-encoded membrane and secreted Ig, was used to confirm that alteration in B cell position previously attributed to changes in follicular composition could be explained on the basis of available antigen concentration, rather than the diversity of the repertoire.

scholarly journals Constitutive Expression of AID Leads to Tumorigenesis

2003 ◽  
Vol 197 (9) ◽  
pp. 1173-1181 ◽  
Author(s):  
Il-mi Okazaki ◽  
Hiroshi Hiai ◽  
Naoki Kakazu ◽  
Shuichi Yamada ◽  
Masamichi Muramatsu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Genome Stability ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Point Mutations ◽  
Constitutive Expression ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Artificial Substrates

Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy.

Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4345-4350 ◽  
Author(s):  
Dörte Bechtel ◽  
Julia Kurth ◽  
Claus Unkel ◽  
Ralf Küppers
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Lymphoproliferative Disease ◽  
Barr Virus ◽  
Classic Hodgkin Lymphoma ◽  
Epstein Barr

In classic Hodgkin lymphoma (HL) and posttransplantation lymphoproliferative disease (PTLD), 2 malignancies frequently associated with Epstein-Barr virus (EBV), the tumor cells often appear to derive from B-cell receptor (BCR)–deficient and therefore preapoptotic germinal center (GC) B cells. To test whether EBV can rescue BCR-less GC B cells, we infected human tonsillar CD77+ GC B cells in vitro with EBV. More than 60 monoclonal lymphoblastoid cell lines (LCLs) were established. Among these, 28 cell lines did not express surface immunoglobulin (sIg). Two of the sIg-negative cell lines carry obviously destructive mutations that have been introduced into originally functional VH gene rearrangements during the process of somatic hypermutation. Quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) showed that in most other lines the sIg deficiency was not simply the result of transcriptional down-regulation, but it was rather due to posttranscriptional defects. These findings strongly support the idea that EBV plays a central role in the pathogenesis of classic HL and PTLD by rescuing BCR-deficient, preapoptotic GC B cells from apoptosis, and that EBV infection renders the cells independent from survival signals normally supplied by a BCR. The monoclonal LCLs represent valuable models for early stages of lymphoma development in classic HL and PTLD.

Antigen-specific activation of B cells in vitro after recruitment of T cell help with superantigen

1995 ◽  
Vol 1 (1) ◽  
pp. 29-39 ◽  
Author(s):  
Sigurdur Ingvarsson ◽  
Ann Catrin Simonsson Lagerkvist ◽  
Christina Mårtensson ◽  
Ulrika Granberg ◽  
Peter Ifversen ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
T Cell Help

scholarly journals Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help

2006 ◽  
Vol 203 (8) ◽  
pp. 1985-1998 ◽  
Author(s):  
Laura Mandik-Nayak ◽  
Jennifer Racz ◽  
Barry P. Sleckman ◽  
Paul M. Allen
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
B Cell Tolerance ◽  
Marginal Zone B Cells ◽  
T Cell Help

In K/BxN mice, arthritis is induced by autoantibodies against glucose-6-phosphate-isomerase (GPI). To investigate B cell tolerance to GPI in nonautoimmune mice, we increased the GPI-reactive B cell frequency using a low affinity anti-GPI H chain transgene. Surprisingly, anti-GPI B cells were not tolerant to this ubiquitously expressed and circulating autoantigen. Instead, they were found in two functionally distinct compartments: an activated population in the splenic marginal zone (MZ) and an antigenically ignorant one in the recirculating follicular/lymph node (LN) pool. This difference in activation was due to increased autoantigen availability in the MZ. Importantly, the LN anti-GPI B cells remained functionally competent and could be induced to secrete autoantibodies in response to cognate T cell help in vitro and in vivo. Therefore, our study of low affinity autoreactive B cells reveals two distinct but potentially concurrent mechanisms for their activation, of which one is T cell dependent and the other is T cell independent.

scholarly journals B Lymphocyte Chemotaxis Regulated in Association with Microanatomic Localization, Differentiation State, and B Cell Receptor Engagement

1998 ◽  
Vol 187 (5) ◽  
pp. 753-762 ◽  
Author(s):  
Conrad C. Bleul ◽  
Joachim L. Schultze ◽  
Timothy A. Springer
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Messenger Rna ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cxc Chemokine

Migration of mature B lymphocytes within secondary lymphoid organs and recirculation between these sites are thought to allow B cells to obtain T cell help, to undergo somatic hypermutation, to differentiate into effector cells, and to home to sites of antibody production. The mechanisms that direct migration of B lymphocytes are unknown, but there is evidence that G protein–coupled receptors, and possibly chemokine receptors, may be involved. Stromal cell– derived factor (SDF)-1α is a CXC chemokine previously characterized as an efficacious chemoattractant for T lymphocytes and monocytes in peripheral blood. Here we show with purified tonsillar B cells that SDF-1α also attracts naive and memory, but not germinal center (GC) B lymphocytes. Furthermore, GC B cells could be converted to respond to SDF-1α by in vitro differentiation into memory B lymphocytes. Conversely, the migratory response in naive and memory B cells was significantly reduced after B cell receptor engagement and CD40 signaling. The receptor for SDF-1, CXC chemokine receptor 4 (CXCR4), was found to be expressed on responsive as well as unresponsive B cell subsets, but was more rapidly downregulated on responsive cells by ligand. Finally, messenger RNA for SDF-1 was detected by in situ hybridization in a layer of cells surrounding the GC. These findings show that responsiveness to the chemoattractant SDF-1α is regulated during B lymphocyte activation, and correlates with positioning of B lymphocytes within a secondary lymphoid organ.

scholarly journals Regulation of B cell fate by chronic activity of the IgE B cell receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zhiyong Yang ◽  
Marcus J Robinson ◽  
Xiangjun Chen ◽  
Geoffrey A Smith ◽  
Jack Taunton ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Plasma Cells ◽  
Cell Receptor ◽  
Culture Conditions ◽  
B Cell Receptor ◽  
Cell Cycles ◽  
T Cell Help

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses.

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 < 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 The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.

1992 ◽  
Vol 176 (4) ◽  
pp. 1091-1098 ◽  
Author(s):  
R A Seder ◽  
W E Paul ◽  
M M Davis ◽  
B Fazekas de St Groth
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Ifn Gamma

To study the factors that determine whether CD4+ T cells produce interleukin 4 (IL-4) or interferon gamma (IFN-gamma) upon stimulation we used a system allowing naive T cells to be primed in vitro by specific antigen. Dense CD4+ T cells were purified from mice that expressed transgenes encoding a T cell receptor specific for pigeon cytochrome C peptide 88-104 in association with I-Ek. These T cells produced very limited amounts of IL-4 and IFN-gamma upon immediate challenge with 88-104 and antigen-presenting cells (APC). However, after an initial "priming" culture in which they were incubated for 4 d in the presence of 88-104, APC, and 1,000 U/ml IL-4, the T cells acquired the capacity to produce substantial amounts of IL-4 upon rechallenge but made very little IFN-gamma. Cells primed in the absence of IL-4 produced IFN-gamma upon rechallenge but virtually no IL-4. The inhibitory effect of IL-4 on IFN-gamma production did not appear to be mediated by the induction of IL-10 production since IL-10 addition to initial cultures did not suppress priming for IFN-gamma production, nor did anti-IL-10 block the inhibitory effect of IL-4. IFN-gamma itself did not increase priming for IFN-gamma production, nor did anti-IFN-gamma reduce such priming. IFN-gamma did, however, diminish priming for IL-4 production when limiting amounts of IL-4 (100 U/ml) were used in the initial culture. The dominant effect of IL-4 in determining the lymphokine-producing phenotype of primed cells was observed with dendritic cells (DC), activated B cells, and I-Ek-transfected fibroblasts as APC. However, the different APC did vary in their potency, with DC being superior to activated B cells, which were superior to transfected fibroblasts.

Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b/CD3 As a Potential Therapy for B Cell Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4507-4507 ◽  
Author(s):  
L. Laura Sun ◽  
Xiaocheng Chen ◽  
Yvonne Chen ◽  
Mark S. Dennis ◽  
Diego Ellerman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Antibody Fragments ◽  
Bispecific Antibodies ◽  
Cell Targeting ◽  
B Cell Malignancies

Abstract T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. As an example, encouraging clinical responses have been reported with the B cell targeting Blinatumomab, a 55-kDa fusion protein composed of two single-chain antibody fragments (scFvs). However, the therapeutic promise of many reported bispecific antibodies and fragments is often limited by unfavorable pharmacokinetics and administration schedule, immunogenicity, and a propensity towards aggregation. We have adopted a knobs-into-holes (KIH) antibody format and produced T-cell dependent bispecific antibodies (TDB), which allow one arm to target various B cell antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. These B cell targeting TDBs are full length, humanized IgG1 antibodies with natural antibody architecture. Single dose pharmacokinetic/pharmacodynamic studies in cynomolgus monkeys show the KIH format TDBs are well tolerated in life, result in potent B cell depletion in peripheral and lymphoid tissue, and demonstrate pharmacokinetic properties resembling conventional antibody therapy. One B cell antigen targeted is CD79b, a component of the B cell receptor complex. CD79b is restricted to B cells, is highly prevalent on B cell leukemia and lymphomas, and has been clinically validated by an anti-CD79b antibody-drug conjugate as a safe and effective therapeutic target for B cell malignancies (ASCO 2014 abstract#8519). In our present work, we show that anti-CD79b/CD3 TDB can be produced and purified from E.coli, free of homodimer and aggregates. Anti-CD79b/CD3 TDB is a conditional agonist, activating CD3+T cells only in the presence of CD79b expressing B cells. In vitro, it induces potent B cell killing in a T-cell dependent manner, and is broadly active against lymphoma cell lines with a wide range of CD79b antigen levels. Compared to bispecific antibodies targeting some other B cell antigens, anti-CD79b/CD3 TDB appears to be more potent in autologous B cell killing assays with human PBMCs isolated from healthy donors. Taking advantage of antibodies with a range of binding affinities, we show that the B cell cytotoxic potency of anti-CD79b/CD3 TDB can be enhanced with increased binding affinity of either the anti-CD79b arm or the anti-CD3 arm in vitro. To assess the therapeutic potential of anti-CD79b/CD3 TDB, we further demonstrate that it is active in killing B lymphoma cells isolated from leukemia and lymphoma patients. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB may be a promising agent for clinical development in B cell malignancies. Disclosures Sun: Genentech: Employment. Chen:Genentech: Employment. Chen:Genentech: Employment. Dennis:Genentech: Employment. Ellerman:Genentech: Employment. Johnson:Genentech: Employment. Mathieu:Genentech: Employment. Oldendorp:Genentech: Employment. Polson:Genentech: Employment. Reyes:Genentech: Employment. Stefanich:Genentech: Employment. Wang:Genentech: Employment. Wang:Genentech: Employment. Zheng:Genentech: Employment. Ebens:Genentech: Employment.

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