Mode of Bioenergetic Metabolism during B Cell Differentiation in the Intestine Determines the Distinct Requirement for Vitamin B1

Kunisawa, Jun; Sugiura, Yuki; Wake, Taichi; Nagatake, Takahiro; Suzuki, Haruo; Nagasawa, Risa; Shikata, Shiori; Honda, Kurara; Hashimoto, Eri; Suzuki, Yuji; Setou, Mitsutoshi; Suematsu, Makoto; Kiyono, Hiroshi

doi:10.1016/j.celrep.2015.08.063

Cited by 95 publications

(87 citation statements)

References 49 publications

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“…It is unclear if T FR cells prevent their upregulation or actively downregulate, these pathways. Our findings are consistent with previous work showing that B cell activation induces glycolysis in B cells, which may aid in antibody production 31, 41 . Glycolysis and the mTOR pathway were also inhibited in T FH cells suppressed by T FR cells.…”

Section: Discussionsupporting

confidence: 93%

Suppression by TFR cells leads to durable and selective inhibition of B cell effector function

et al. 2016

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T follicular regulatory (TFR) cells inhibit T follicular helper (TFH) cell-mediated antibody production. The mechanisms by which TFR cells exert their key immunoregulatory functions are largely unknown. Here we show that TFR cells induce a distinct suppressive state in TFH and B cells, in which effector transcriptional signatures are maintained, but key effector molecules and metabolic pathways are suppressed. TFR cell suppression of B cell antibody production and metabolism is durable, and persists even in the absence of TFR cells. This durable suppression is due, in part, to epigenetic changes. IL-21 can overcome TFR cell-mediated suppression, inhibiting TFR cells and stimulating B cells. By determining mechanisms of TFR cell-mediated suppression, we have identified methods for modulating TFR cell function and antibody production.

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Section: Discussionsupporting

confidence: 93%

Suppression by TFR cells leads to durable and selective inhibition of B cell effector function

et al. 2016

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“…Until recently, two reports have suggested that BCR-or LPSactivated B cells and IgA + plasma cells adopt both glycolysis and oxidative phosphorylation to maintain cell growth and function (10,11). Consistent with these findings, our present study shows that Hcy stimulation causes an increase in both glycolytic and oxidative metabolic rates in B cells.…”

Section: Discussionsupporting

confidence: 81%

“…Although B cells share several features with T cells, it has recently been reported that B cells increase their rate of both glycolysis and oxidative phosphorylation in a relatively balanced fashion upon BCR or LPS stimulation (10). Moreover, in the intestinal immune system, IgA + plasma cells in the intestinal lamina propria use both glycolytic and oxidative metabolism, whereas naive B cells in Peyer's patches preferentially use oxidative metabolism (11). These investigations have revealed an important role of metabolic reprogramming in B cell activation.…”

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confidence: 99%

Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming

Deng

Liu

et al. 2017

The Journal of Immunology

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The overactivation of immune cells plays an important role in the pathogenesis of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Homocysteine (Hcy) activates B cell proliferation and Ab secretion; however, the underlying mechanisms for these effects remain largely unknown. Metabolic reprogramming is critical for lymphocyte activation and effector function. In this study, we showed that Hcy-activated B cells displayed an increase in both oxidative phosphorylation and glycolysis, with a tendency to shift toward the latter, as well as an accumulation of intermediates in the pentose phosphate pathway, to provide energy and biosynthetic substrates for cell growth and function. Mechanistically, Hcy increased both the protein expression and glycolytic enzyme activity of the pyruvate kinase muscle isozyme 2 (PKM2) in B cells, whereas the PKM2 inhibitor shikonin restored Hcy-induced metabolic changes, as well as B cell proliferation and Ab secretion both in vivo and in vitro, indicating that PKM2 plays a critical role in metabolic reprogramming in Hcy-activated B cells. Further investigation revealed that the Akt–mechanistic target of rapamycin signaling pathway was involved in this process, as the mechanistic target of rapamycin inhibitor rapamycin inhibited Hcy-induced changes in PKM2 enzyme activity and B cell activation. Notably, shikonin treatment effectively attenuated HHcy-accelerated atherosclerotic lesion formation in apolipoprotein E–deficient mice. In conclusion, our results demonstrate that PKM2 is required to support metabolic reprogramming for Hcy-induced B cell activation and function, and it might serve as a critical regulator in HHcy-accelerated initiation of atherosclerosis.

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“…Comparison of naïve B cells in the intestinal Peyer’s patches with IgA producing cells in the intestinal lamina propria have shown that a change of energy metabolism occurs during differentiation of B cells into IgA-producing cells (15). Hence, while both naïve and IgA-producing cells use the tricarboxylic acid cycle and fatty acid for energy production, glycolysis preferentially occur in IgA-producing cells (15). Immunoglobulin CSR and production of IgA can occur via T-independent or T-dependent mechanisms depending on the nature of antigen and the cellular origin of help received by B cells (Figure 1).…”

Section: Iga and Secretory Igamentioning

confidence: 99%

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

Boyaka

2017

The Journal of Immunology

175

155

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Mucosal IgA or secretory IgA (SIgA) are structurally equipped to resist chemical degradation in the harsh environment of mucosal surfaces and the enzymes of host or microbial origin. Production of SIgA is finely regulated and distinct T-independent and T-dependent mechanisms orchestrate immunoglobulin heavy chain α class switching and SIgA responses against commensal and pathogenic microbes. Most infectious pathogens enter the host via mucosal surfaces. To provide a first line of protection at these entry ports, vaccines are being developed to induce pathogen-specific SIgA in addition to systemic immunity achieved by injected vaccines. Mucosal or epicutaneous delivery of vaccines helps target the inductive sites for IgA responses. The efficacy of such vaccines relies on the identification/engineering of vaccine adjuvants capable of supporting the development of SIgA alongside systemic immunity and delivery systems that improve vaccine delivery to the targeted anatomic sites and immune cells.

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Mode of Bioenergetic Metabolism during B Cell Differentiation in the Intestine Determines the Distinct Requirement for Vitamin B1

Cited by 95 publications

References 49 publications

Suppression by TFR cells leads to durable and selective inhibition of B cell effector function

Suppression by TFR cells leads to durable and selective inhibition of B cell effector function

Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

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