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Cancer Research Sep 2017CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited...
CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. .
Topics: Adult; Aged; Animals; Apoptosis; B-Lymphocytes; Biomarkers, Tumor; CD28 Antigens; CTLA-4 Antigen; Cell Proliferation; Female; Humans; Lymphocyte Activation; Lymphoma, B-Cell; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Neoplasm Staging; Prognosis; STAT3 Transcription Factor; Signal Transduction; T-Lymphocytes; TYK2 Kinase; Tumor Cells, Cultured
PubMed: 28716895
DOI: 10.1158/0008-5472.CAN-16-0342 -
Cells May 2021Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to...
Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton's tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.
Topics: Agammaglobulinaemia Tyrosine Kinase; Arthritis, Rheumatoid; B-Lymphocytes; Humans; Idiopathic Pulmonary Fibrosis; Lymphocyte Activation; Phospholipase C gamma; Protein Kinase Inhibitors; Protein-Tyrosine Kinases
PubMed: 34073225
DOI: 10.3390/cells10061321 -
Cell Death & Disease Oct 2020BAFF supports B-cell survival and homeostasis by activating the NF-κB pathway. While NF-κB is also involved in the priming signal of NLRP3 inflammasome, the role of...
BAFF supports B-cell survival and homeostasis by activating the NF-κB pathway. While NF-κB is also involved in the priming signal of NLRP3 inflammasome, the role of BAFF in NLRP3 inflammasome regulation is unknown. Here we report BAFF engagement to BAFF receptor elicited both priming and activating signals for NLRP3 inflammasomes in primary B cells and B lymphoma cell lines. This induction of NLRP3 inflammasomes by BAFF led to increased NLRP3 and IL-1β expression, caspase-1 activation, IL-1β secretion, and pyroptosis. Mechanistically, BAFF activated NLRP3 inflammasomes by promoting the association of cIAP-TRAF2 with components of NLRP3 inflammasomes, and by inducing Src activity-dependent ROS production and potassium ion efflux. B-cell receptor (BCR) stimulation on the Lyn signaling pathway inhibited BAFF-induced Src activities and attenuated BAFF-induced NLRP3 inflammasome activation. These findings reveal an additional function of BAFF in B-cell homeostasis that is associated with BCR activities.
Topics: B-Cell Activating Factor; B-Lymphocytes; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 33004801
DOI: 10.1038/s41419-020-03035-2 -
Seminars in Immunology Aug 2008B lymphocytes are generated from hematopoietic stem cells in a series of steps controlled by transcription factors. One of the most important regulators of this process... (Review)
Review
B lymphocytes are generated from hematopoietic stem cells in a series of steps controlled by transcription factors. One of the most important regulators of this process is early B cell factor (EBF). Multiple lines of evidence indicate that expression of EBF is a principle determinant of the B cell fate. In the absence of EBF, progenitor cells fail to express classical markers of B cells, including immunoglobulins. EBF drives B cell differentiation by activating the Pax5 gene and other genes required for the pre-B and B cell receptors. New evidence suggests that expression of EBF in common lymphoid progenitors directs B cell fate decisions. Specification and commitment of cells to the B cell lineage are further established by Pax5, which increases expression of EBF. Recently, it was demonstrated that both EBF and Pax5 contribute to the commitment of cells to the B lineage. Together, these studies confirm that EBF is a keystone in the regulatory network that coordinates B cell lineage specification and commitment.
Topics: Animals; B-Cell Activating Factor; B-Lymphocytes; Cell Differentiation; Cell Lineage; Humans; PAX5 Transcription Factor; Trans-Activators
PubMed: 18722139
DOI: 10.1016/j.smim.2008.07.004 -
Journal of Immunology (Baltimore, Md. :... Nov 2018B cells undergo epigenetic remodeling as they differentiate into Ab-secreting cells (ASC). LSD1 is a histone demethylase known to decommission active enhancers and...
B cells undergo epigenetic remodeling as they differentiate into Ab-secreting cells (ASC). LSD1 is a histone demethylase known to decommission active enhancers and cooperate with the ASC master regulatory transcription factor Blimp-1. The contribution of LSD1 to ASC formation is poorly understood. In this study, we show that LSD1 is necessary for proliferation and differentiation of mouse naive B cells (nB) into plasmablasts (PB). Following LPS inoculation, LSD1-deficient hosts exhibited a 2-fold reduction of splenic PB and serum IgM. LSD1-deficient PB exhibited derepression and superinduction of genes involved in immune system processes; a subset of these being direct Blimp-1 target-repressed genes. Cell cycle genes were globally downregulated without LSD1, which corresponded to a decrease in the proliferative capacity of LSD1-deficient activated B cells. PB lacking LSD1 displayed increased histone H3 lysine 4 monomethylation and chromatin accessibility at nB active enhancers and the binding sites of transcription factors Blimp-1, PU.1, and IRF4 that mapped to LSD1-repressed genes. Together, these data show that LSD1 is required for normal in vivo PB formation, distinguish LSD1 as a transcriptional rheostat and epigenetic modifier of B cell differentiation, and identify LSD1 as a factor responsible for decommissioning nB active enhancers.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Cell Proliferation; Histone Demethylases; Mice; Plasma Cells
PubMed: 30232138
DOI: 10.4049/jimmunol.1800952 -
Immunity Apr 2009Pax5 is an essential regulator of B cell identity and function. Here, we used transgenesis and deletion mapping to identify a potent enhancer in intron 5 of the Pax5...
Pax5 is an essential regulator of B cell identity and function. Here, we used transgenesis and deletion mapping to identify a potent enhancer in intron 5 of the Pax5 locus. This enhancer in combination with the promoter region was sufficient to recapitulate the B lymphoid expression of Pax5. The enhancer was silenced by DNA methylation in embryonic stem cells, but became activated in multipotent hematopoietic progenitors. It contained functional binding sites for the transcription factors PU.1, IRF4, IRF8, and NF-kappaB, suggesting that these regulators contribute to sequential enhancer activation in hematopoietic progenitors and during B cell development. In contrast, the promoter region was repressed by Polycomb group proteins in non-B cells and was activated only at the onset of pro-B cell development through induction of chromatin remodeling by the transcription factor EBF1. These experiments demonstrate a stepwise activation of Pax5 in early lymphopoiesis and provide mechanistic insights into the process of B cell commitment.
Topics: Animals; B-Lymphocytes; Base Sequence; Chromosomes, Artificial, Bacterial; Enhancer Elements, Genetic; Flow Cytometry; Gene Expression Regulation; Humans; Lymphopoiesis; Mice; Molecular Sequence Data; PAX5 Transcription Factor; Promoter Regions, Genetic; Trans-Activators; Transgenes; Up-Regulation
PubMed: 19345119
DOI: 10.1016/j.immuni.2009.01.012 -
PLoS Biology Oct 2010Chromosomal translocations between loci encoding MALT1 and c-IAP2 are common in MALT lymphomas. The resulting fusion proteins lack the c-IAP2 RING domain, the region...
Chromosomal translocations between loci encoding MALT1 and c-IAP2 are common in MALT lymphomas. The resulting fusion proteins lack the c-IAP2 RING domain, the region responsible for its ubiquitin protein ligase (E3) activity. Ectopic expression of the fusion protein activates the canonical NF-κB signaling cascade, but how it does so is controversial and how it promotes MALT lymphoma is unknown. Considering recent reports implicating c-IAP1 and c-IAP2 E3 activity in repression of non-canonical NF-κB signaling, we asked if the c-IAP2/MALT fusion protein can initiate non-canonical NF-κB activation. Here we show that in addition to canonical activation, the fusion protein stabilizes NIK and activates non-canonical NF-κB. Canonical but not non-canonical activation depended on MALT1 paracaspase activity, and expression of E3-inactive c-IAP2 activated non-canonical NF-κB. Mice in which endogenous c-IAP2 was replaced with an E3-inactive mutant accumulated abnormal B cells with elevated non-canonical NF-κB and had increased numbers of B cells with a marginal zone phenotype, gut-associated lymphoid hyperplasia, and other features of MALT lymphoma. Thus, the c-IAP2/MALT1 fusion protein activates NF-κB by two distinct mechanisms, and loss of c-IAP2 E3 activity in vivo is sufficient to induce abnormalities common to MALT lymphoma.
Topics: Animals; B-Lymphocytes; Cell Proliferation; Cell Survival; Gene Knock-In Techniques; Humans; Inhibitor of Apoptosis Proteins; Lymphoma, B-Cell, Marginal Zone; Mice; Mice, Transgenic; NF-kappa B; Recombinant Fusion Proteins; Translocation, Genetic; Ubiquitin-Protein Ligases
PubMed: 21048983
DOI: 10.1371/journal.pbio.1000518 -
Frontiers in Bioscience (Scholar... Jan 2012A number of microorganisms are capable of binding immunoglobulins (Igs) in a manner, which excludes binding to conventional antigen binding sites. Interaction of such... (Review)
Review
A number of microorganisms are capable of binding immunoglobulins (Igs) in a manner, which excludes binding to conventional antigen binding sites. Interaction of such bacterial proteins with surface immunoglobulins leads to polyclonal activation of B-lymphocytes. A recent example is Moraxella catarrhalis that binds to B lymphocytes in an IgD-dependent manner and induces proliferation and differentiation of B lymphocytes leading to the production of unspecific Igs. The activation is mediated by Moraxella IgD binding protein (MID), which specifically binds to both soluble IgD and the IgD B cell receptor (BCR). Besides cross-linking the BCR, whole Moraxella and outer membrane vesicles (OMVs) engage Toll like receptors (TLRs) to further increase the response. TLR activation leads to initiation of signaling pathways, which evoke a proinflammatory response against the invading microbes. Polyclonal B cell activation has in general been implicated in various phenomenons that are detrimental for the host but beneficial for pathogens, for example, autoimmune manifestations and redirection of the immune system.
Topics: Animals; Antigens, Bacterial; B-Lymphocytes; Humans; Immunoglobulin D; Lymphocyte Activation; Moraxella catarrhalis; Signal Transduction; Superantigens; Toll-Like Receptors; alpha-Macroglobulins
PubMed: 22202107
DOI: 10.2741/s316 -
Trends in Immunology May 2014In B cell progenitors, E-proteins E2A and HEB (HeLa E-box binding protein) are crucial for the induction of a B lineage-specific program of gene expression and for... (Review)
Review
In B cell progenitors, E-proteins E2A and HEB (HeLa E-box binding protein) are crucial for the induction of a B lineage-specific program of gene expression and for orchestrating the assembly of the immunoglobulin loci. In the thymus E2A and HEB act differently, activating the expression of genes closely associated with the establishment of T cell identity and promoting the rearrangement of T cell receptor (TCR) loci. These findings have raised the question as to how E-proteins exert these different activities. We review here the distinct regulatory networks that establish B versus T cell identity, and how genomic architecture and location of genes is modulated in these lineage decisions. We conclude by proposing a model wherein stochasticity in the nuclear location of the early B cell factor 1 (Ebf1) locus in multipotent progenitors determines this lineage choice.
Topics: Alleles; Animals; B-Lymphocytes; Cell Differentiation; Cell Lineage; Gene Expression Regulation; Gene Regulatory Networks; Genome; Humans; T-Lymphocytes; Transcription, Genetic
PubMed: 24679436
DOI: 10.1016/j.it.2014.02.009 -
Frontiers in Immunology 2020Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered... (Clinical Trial)
Clinical Trial
Interferon Enhances B Cell Activation Associated With FOXM1 Induction: Potential Novel Therapeutic Strategy for Targeting the Plasmablasts of Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38CD43 B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFN on B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFN promoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFN preferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferon . This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.
Topics: Adult; B-Lymphocytes; Female; Forkhead Box Protein M1; Gene Expression Regulation; Humans; Immunologic Memory; Interferon-alpha; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Middle Aged
PubMed: 33633721
DOI: 10.3389/fimmu.2020.498703