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Journal For Immunotherapy of Cancer Dec 2022B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However,...
BACKGROUND
B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood.
METHODS
We investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing.
RESULTS
Here we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells in a cell-cell contact dependent manner by consuming more oxygen via an increase in their oxidative phosphorylation (OXPHOS). Moreover, activated B cells deprived T cells of glucose and produced lactic acid through their high glycolytic activity. Activated B cells thus inhibited the mammalian target of rapamycin pathway in T cells, resulting in suppression of T-cell cytokine production and proliferation. Finally, we confirmed the presence of tumor-associated B cells with high glycolytic and OXPHOS activities in patients with melanoma, associated with poor response to immune checkpoint blockade therapy.
CONCLUSIONS
We have revealed for the first time the immunomodulatory effects of the metabolic activity of activated B cells and their possible role in suppressing antitumor T-cell responses. These findings add novel insights into immunometabolism and have important implications for cancer immunotherapy.
Topics: T-Lymphocytes; B-Lymphocytes; Immunosuppressive Agents; Sirolimus; Immunotherapy
PubMed: 36543374
DOI: 10.1136/jitc-2022-005644 -
Frontiers in Immunology 2020Adjuvants enhance magnitude and duration of immune responses induced by vaccines. In this study we assessed in neonatal mice if and how the adjuvant LT-K63 given with a...
Adjuvants enhance magnitude and duration of immune responses induced by vaccines. In this study we assessed in neonatal mice if and how the adjuvant LT-K63 given with a pneumococcal conjugate vaccine, Pnc1-TT, could affect the expression of tumor necrosis factor receptor (TNF-R) superfamily members, known to be involved in the initiation and maintenance of antibody responses; B cell activating factor receptor (BAFF-R) and B cell maturation antigen (BCMA) and their ligands, BAFF, and a proliferation inducing ligand (APRIL). Initially we assessed the maturation status of different B cell populations and their expression of BAFF-R and BCMA. Neonatal mice had dramatically fewer B cells than adult mice and the composition of different subsets within the B cell pool differed greatly. Proportionally newly formed B cells were most abundant, but they had diminished BAFF-R expression which could explain low proportions of marginal zone and follicular B cells observed. Limited BCMA expression was also detected in neonatal pre-plasmablasts/plasmablasts. LT-K63 enhanced vaccine-induced BAFF-R expression in splenic marginal zone, follicular and newly formed B cells, leading to increased plasmablast/plasma cells, and their enhanced expression of BCMA in spleen and bone marrow. Additionally, the induction of BAFF and APRIL expression occurred early in neonatal mice immunized with Pnc1-TT either with or without LT-K63. However, BAFF and APRIL cells in spleens were maintained at a higher level in mice that received the adjuvant. Furthermore, the early increase of APRIL cells in bone marrow was more profound in mice immunized with vaccine and adjuvant. Finally, we assessed, for the first time in neonatal mice, accessory cells of the plasma cell niche in bone marrow and their secretion of APRIL. We found that LT-K63 enhanced the frequency and APRIL expression of eosinophils, macrophages, and megakaryocytes, which likely contributed to plasma cell survival, even though APRIL cells showed a fast decline. All this was associated with enhanced, sustained vaccine-specific antibody-secreting cells in bone marrow and persisting vaccine-specific serum antibodies. Our study sheds light on the mechanisms behind the adjuvanticity of LT-K63 and identifies molecular pathways that should be triggered by vaccine adjuvants to induce sustained humoral immunity in early life.
Topics: Animals; Animals, Newborn; B-Lymphocytes; Bacterial Toxins; Enterotoxins; Escherichia coli Proteins; Immunity, Humoral; Lymphocyte Activation; Mice
PubMed: 33193301
DOI: 10.3389/fimmu.2020.527310 -
Nature Jul 2020Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer. Here we analyse 1,148 patient-derived B-cell...
Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5) or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK). STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.
Topics: Animals; B-Lymphocytes; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Leukemia, B-Cell; Mice; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-myc; STAT5 Transcription Factor; Signal Transduction
PubMed: 32699415
DOI: 10.1038/s41586-020-2513-4 -
Genes & Development Jan 2018Earlier studies have identified transcription factors that specify B-cell fate, but the underlying mechanisms remain to be revealed. Two new studies by Miyai and... (Review)
Review
Earlier studies have identified transcription factors that specify B-cell fate, but the underlying mechanisms remain to be revealed. Two new studies by Miyai and colleagues (pp. 112-126) and Li and colleagues (pp. 96-111) in this issue of provide new and unprecedented insights into the genetic and epigenetic mechanisms that establish B-cell identity.
Topics: B-Lymphocytes; Cell Differentiation; Lymphocyte Activation; Trans-Activators; Transcription Factors
PubMed: 29449365
DOI: 10.1101/gad.311357.118 -
Clinical and Experimental Immunology Nov 2014The biologically active form of vitamin D3 , 1, 25-dihydroxyvitamin D3 (calcitriol), is a potent modulator of the immune response. We have shown previously that...
The biologically active form of vitamin D3 , 1, 25-dihydroxyvitamin D3 (calcitriol), is a potent modulator of the immune response. We have shown previously that calcitriol modulates the immunoglobulin response in vitro and in vivo in mice and humans. To analyse the underlying molecular mechanisms we studied whether calcitriol-primed B cells modulate T cell activation and function. Human B cells were stimulated with anti-CD40 and interleukin (IL)-4 in the presence of increasing concentrations of calcitriol. After removal of calcitriol, primed B cells were co-cultured with autologous CD4(+) T cells; the B cell phenotype T cell activation and their consecutive cytokine production were also assessed. Naive T cells co-cultured with calcitriol-primed naive B cells showed a reduced expansion, nuclear factor of activated T cells, cytoplasmic 2 (NFATc2) expression and cytokine production upon restimulation. CD86 expression on B cells after calcitriol priming was identified as an underlying mechanism, as T cell activation and expansion was rescued by activating anti-CD28 antibodies. Our data indicate that calcitriol-primed B cells display an impaired capacity to activate T cells. Taken together, we identified a novel B cell-dependent vitamin D immune regulatory mechanism, namely by decreased co-stimulation of calcitriol-primed B cells.
Topics: Antibodies, Monoclonal; B-Lymphocytes; CD28 Antigens; Calcitriol; Cells, Cultured; Cytokines; Gene Expression; Humans; Immunophenotyping; Lymphocyte Activation; T-Lymphocytes
PubMed: 24965738
DOI: 10.1111/cei.12406 -
International Immunopharmacology Jul 2021B-cell activating factor (BAFF) is an essential cytokine for B-cell maturation, differentiation and survival, and excess BAFF induces aggressive or neoplastic B-cell...
B-cell activating factor (BAFF) is an essential cytokine for B-cell maturation, differentiation and survival, and excess BAFF induces aggressive or neoplastic B-cell disorders and contributes to development of autoimmune diseases. Metformin, an anti-diabetic drug, has recently garnered a great attention due to its anti-proliferative and immune-modulatory features. However, little is known regarding the effect of metformin on BAFF-stimulated B cells. Here, we show that metformin attenuated human soluble BAFF (hsBAFF)-induced cell proliferation and survival by blocking the Erk1/2 pathway in normal and B-lymphoid (Raji) cells. Pretreatment with U0126, knockdown of Erk1/2, or expression of dominant negative MKK1 strengthened metformin's inhibition of hsBAFF-activated Erk1/2 and B-cell proliferation/viability, whereas expression of constitutively active MKK1 rendered high resistance to metformin. Further investigation found that overexpression of wild type PTEN or ectopic expression of dominant negative Akt potentiated metformin's suppression of hsBAFF-induced Erk1/2 activation and proliferation/viability in Raji cells, implying a PTEN/Akt-dependent mechanism involved. Furthermore, we noticed that metformin hindered hsBAFF-activated mTOR pathway in B cells. Inhibition of mTOR with rapamycin or knockdown of mTOR enhanced metformin's suppression of hsBAFF-induced phosphorylation of S6K1, PTEN, Akt, and Erk1/2, as well as B-cell proliferation/viability. These results indicate that metformin prevents BAFF activation of Erk1/2 from cell proliferation and survival by impeding mTOR-PTEN/Akt signaling pathway in normal and neoplastic B-lymphoid cells. Our findings support that metformin has a great potential for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.
Topics: Animals; B-Cell Activating Factor; B-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Hypoglycemic Agents; Lymphocyte Activation; Metformin; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; PTEN Phosphohydrolase; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 34004440
DOI: 10.1016/j.intimp.2021.107771 -
Biomedical Journal 2013Activation-induced deaminase (AID), a member of the AID/apolipoprotein B mRNA-editing enzyme-catalytic (APOBEC) family, deaminates DNA cytidines into uridines and is the... (Review)
Review
Activation-induced deaminase (AID), a member of the AID/apolipoprotein B mRNA-editing enzyme-catalytic (APOBEC) family, deaminates DNA cytidines into uridines and is the major trans-acting player of immunoglobulin (Ig) genes' diversification in mature B lymphocytes. It allows multiple antigen-driven Ig modifications through gene conversion and/or somatic hypermutation of variable region genes and also permits to switch from IgM expression to other antibody classes after class switch recombination, or to stop Ig expression after locus suicide recombination. AID is expressed at high levels into germinal center activated B cells with a very stringent temporal and spatial regulation. Despite multiple levels of regulation, off-target effects of AID are quite frequent in the B cell lineage and can affect a number of non-Ig genes, albeit at lower level than Ig genes. Beyond the immune system, AID also contributes to cytosine demethylation in undifferentiated cells by deaminating methylcytosines into thymines which are further processed by thymidine glycosylase. This contributes to the maintenance of pluripotency and to the limitation of genetic imprinting. Since AID attacks on DNA can induce replication errors, base excision repair, or mismatch repair, they are strongly mutagenic and are also driving forces of tumorigenesis, not only in B cell malignancies but also in some non-lymphoid tumors involving ectopic AID expression.
Topics: APOBEC-1 Deaminase; Animals; B-Lymphocytes; Cell Differentiation; Cytidine Deaminase; DNA Mismatch Repair; Germinal Center; Humans; Immunoglobulin Class Switching
PubMed: 24385067
DOI: 10.4103/2319-4170.113191 -
Seminars in Cancer Biology Dec 2013The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a... (Review)
Review
The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway. Hepatitis C virus infection can lead to the development of splenic marginal zone lymphoma, while Helicobacter pylori infection is associated with the development of mucosa-associated lymphoid tissue lymphomas. In some of these cases, successful treatment of the infection removes the inciting antigen and results in resolution of the lymphoma. Chronic lymphocytic leukemia has been recognized for decades as a malignancy of auto-reactive B-cells and its clinical course is in part determined by the differential response of the malignant cells to BCR activation. In a number of B-cell malignancies, activating mutations in signal transduction components of the BCR pathway have been identified; prominent examples are activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCL) that carry mutations in CD79B and CARD11 and display chronic active BCR signaling resulting in constitutive activation of the NF-κB pathway. Despite considerable heterogeneity in biology and clinical course, many mature B-cell malignancies are highly sensitive to kinase inhibitors that disrupt BCR signaling. Thus, targeted therapy through inhibition of BCR signaling is emerging as a new treatment paradigm for many B-cell malignancies. Here, we review the role of the BCR in the pathogenesis of B-cell malignancies and summarize clinical results of the emerging class of kinase inhibitors that target this pathway.
Topics: Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; CARD Signaling Adaptor Proteins; CD79 Antigens; Enzyme Inhibitors; Guanylate Cyclase; Humans; Lymphoma; Molecular Targeted Therapy; Mutation; Phosphoinositide-3 Kinase Inhibitors; Protein-Tyrosine Kinases; Receptors, Antigen, B-Cell; Signal Transduction
PubMed: 24060900
DOI: 10.1016/j.semcancer.2013.09.001 -
Cell Calcium Sep 2020B lymphocytes are an important component of the adaptive and innate immune system because of their ability to secrete antibodies and to present antigens to T cells,...
B lymphocytes are an important component of the adaptive and innate immune system because of their ability to secrete antibodies and to present antigens to T cells, which is critical for immune responses to many pathogens. Abnormal B cell function is the cause of diseases including autoimmune, paraneoplastic, and immunodeficiency disorders. The development, survival, and function of B cells depend on signaling through the B cell receptor (BCR) and costimulatory receptors. One of the signaling pathways induced by antigen binding to the BCR is store-operated Ca entry (SOCE), which depends on the Ca channel ORAI1 and its activators stromal interaction molecule (STIM) 1 and 2. A recent study by Berry et al. [1] reports that B cells lacking STIM1 and STIM2 fail to survive and proliferate because abolished SOCE results in impaired expression of two key anti-apoptotic genes and blunted activation of mTORC1 and c-Myc signaling. The associated Ca regulated checkpoints of B cell survival and proliferation can be bypassed, at least partially, by costimulation through CD40 or TLR9. This study provides important new insights on how SOCE controls B cell function.
Topics: Animals; B-Lymphocytes; Calcium; Calcium Signaling; Cell Proliferation; Cell Survival; Humans; Immunity, Humoral; Mice
PubMed: 32563861
DOI: 10.1016/j.ceca.2020.102227 -
Critical Reviews in Biochemistry and... Sep 2016B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines.... (Review)
Review
B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprograming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor-mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes.
Topics: Animals; Autophagy; B-Lymphocytes; Cell Differentiation; Cell Proliferation; Humans; Metabolic Networks and Pathways; Mitochondria; Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 27494162
DOI: 10.1080/10409238.2016.1215288