Progressive Upregulation of Oxidative Metabolism Facilitates Plasmablast Differentiation to a T-Independent Antigen

Price, Madeline J.; Patterson, Dillon G.; Scharer, Christopher D.; Boss, Jeremy M.

doi:10.1016/j.celrep.2018.05.053

Cited by 116 publications

(123 citation statements)

References 32 publications

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“…Multiple metabolic pathways have been associated to the ASC differentiation, such as glycolysis, oxidative phosphorylation, glucose uptake, inositol phosphate, and sterol metabolisms (43,44). Furthermore, the DENV infection can stimulate the activation of the tryptophan metabolism.…”

Section: Discussionmentioning

confidence: 99%

Flavivirus-Mediating B Cell Differentiation Into Antibody-Secreting Cells in Humans Is Associated With the Activation of the Tryptophan Metabolism

et al. 2020

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Patients infected with the Dengue virus (DENV) often present with a massive generation of DENV-specific antibody-secreting cells (ASCs) in the blood. In some cases, these ASCs represent more than 50% of the circulating B cells, a higher magnitude than those induced by other infections, vaccinations, and plasma cell lymphomas. However, it remains unclear how the DENV infection elicits this colossal response. To address this issue, we utilised an in vitro strategy to induce human PBMCs of healthy individuals incubated with DENV particles (DENV4 TVP/360) to differentiate into ASCs. As controls, PBMCs were incubated with a mitogen cocktail or supernatants of uninfected C6/36 cells (mock). The ASC phenotype and function were increasingly detected in the DENV and mitogen-cultured PBMCs as compared to mock-treated cells. In contrast to the in vivo condition, secreted IgG derived from the PBMC-DENV culture was not DENV-specific. Lower ASC numbers were observed when inactivated viral particles or purified B cells were added to the cultures. The physical contact was essential between B cells and the remaining PBMCs for the DENV-mediated ASC response. Considering the evidence for the activation of the tryptophan metabolism detected in the serum of Dengue patients, we assessed its relevance in the DENV-mediated ASC differentiation. For this, tryptophan and its respective metabolites were quantified in the supernatants of cell cultures through mass spectrophotometry. Tryptophan depletion and kynurenine accumulation were found in the supernatants of PBMC-DENV cultures, which presented enhanced detection of indoleamine 2,3-dioxygenase 1 and 2 transcripts as compared to controls. In PBMC-DENV cultures, tryptophan and kynurenine levels strongly correlated to the respective ASC numbers, while the kynurenine levels were directly proportional to the secreted IgG titers. Contrastingly, PBMCs incubated with Zika or attenuated Bonezi et al. Dengue-Mediated Antibody-Secreting Cell DifferentiationYellow Fever viruses showed no correlation between their kynurenine concentrations and ASC numbers. Therefore, our data revealed the existence of distinct pathways for the DENV-mediated ASC differentiation and suggest the involvement of the tryptophan metabolism in this cellular process triggered by flavivirus infections.

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Section: Discussionmentioning

confidence: 99%

Flavivirus-Mediating B Cell Differentiation Into Antibody-Secreting Cells in Humans Is Associated With the Activation of the Tryptophan Metabolism

et al. 2020

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“…While naive, resting B cells have a considerably low metabolic profile, they elevate their metabolic rates upon activation, which is typically manifested by an increase in oxygen consumption and glycolysis (48)(49)(50)(51). The mitogenic stimuli IgM, LPS, and CpG have been shown to dramatically increase metabolic requirements of B cells, playing a key role in this transition, essential for differentiation into antibody secreting cells and productive immune responses (50,52).…”

Section: Discussionmentioning

confidence: 99%

Missing-in-Metastasis/Metastasis Suppressor 1 Regulates B Cell Receptor Signaling, B Cell Metabolic Potential, and T Cell-Independent Immune Responses

et al. 2020

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Efficient generation of antibodies by B cells is one of the prerequisites of protective immunity. B cell activation by cognate antigens via B cell receptors (BCRs), or pathogen-associated molecules through pattern-recognition receptors, such as Toll-like receptors (TLRs), leads to transcriptional and metabolic changes that ultimately transform B cells into antibody-producing plasma cells or memory cells. BCR signaling and a number of steps downstream of it rely on coordinated action of cellular membranes and the actin cytoskeleton, tightly controlled by concerted action of multiple regulatory proteins, some of them exclusive to B cells. Here, we dissect the role of Missing-In-Metastasis (MIM), or Metastasis suppressor 1 (MTSS1), a cancer-associated membrane and actin cytoskeleton regulating protein, in B cell-mediated immunity by taking advantage of MIM knockout mouse strain. We show undisturbed B cell development and largely normal composition of B cell compartments in the periphery. Interestingly, we found that MIM −/− B cells are defected in BCR signaling in response to surface-bound antigens but, on the other hand, show increased metabolic activity after stimulation with LPS or CpG. In vivo, MIM knockout animals exhibit impaired IgM antibody responses to immunization with T cell-independent antigen. This study provides the first comprehensive characterization of MIM in B cells, demonstrates its regulatory role for B cell-mediated immunity, as well as proposes new functions for MIM in tuning receptor signaling and cellular metabolism, processes, which may also contribute to the poorly understood functions of MIM in cancer.

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“…B-cell activation depends heavily on mitochondrial respiration and oxidative phosphorylation. 12,13 We assessed mitochondrial respiration in resting and activated B cells from patients and controls by using extracellular flux analysis, a well-established method for measuring mitochondrial OCR as an indicator of mitochondrial function. [14][15][16] In this assay, the addition of oligomycin inhibits the ATP synthase, revealing the basal OCR generated by the mitochondrial electron transport chain.…”

Section: Ak2 G100s and Ak2 A182d Variants Impair B-cell Function And mentioning

confidence: 99%

“…The mitochondrial OCR was intact in resting AK2 A182D B cells (see Fig E6, A and B in this article's Online Repository at www.jacionline.org). Similar to CD401IL-21 activation, 12 EBV infection of B cells is known to result in increased oxidative phosphorylation and glycolysis to meet the increased metabolic demands of proliferation. 21 This is indicated by the higher basal respiration of control EBV-transformed B cells compared with that of control primary B cells stimulated by anti-CD401IL-21 ( Fig 2, D and Fig 3, A).…”

Section: Ak2 G100s and Ak2 A182d Variants Impair B-cell Function And mentioning

confidence: 99%

Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation

Chou

Alazami

Jaber

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: The gene AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival. Objective: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection. Methods: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function. Results: We identified 2 different homozygous variants in AK2. AK2 G100S and AK2 A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function. Conclusions: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.

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Progressive Upregulation of Oxidative Metabolism Facilitates Plasmablast Differentiation to a T-Independent Antigen

Cited by 116 publications

References 32 publications

Flavivirus-Mediating B Cell Differentiation Into Antibody-Secreting Cells in Humans Is Associated With the Activation of the Tryptophan Metabolism

Flavivirus-Mediating B Cell Differentiation Into Antibody-Secreting Cells in Humans Is Associated With the Activation of the Tryptophan Metabolism

Missing-in-Metastasis/Metastasis Suppressor 1 Regulates B Cell Receptor Signaling, B Cell Metabolic Potential, and T Cell-Independent Immune Responses

Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation

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