Metabolic Program of Regulatory B Lymphocytes and Influence in the Control of Malignant and Autoimmune Situations

Abstract

Metabolic pathways have been studied for a while in eukaryotic cells. During glycolysis, glucose enters into the cells through the Glut1 transporter to be phosphorylated and metabolized generating ATP molecules. Immune cells can use additional pathways to adapt their energetic needs. The pentose phosphate pathway, the glutaminolysis, the fatty acid oxidation and the oxidative phosphorylation generate additional metabolites to respond to the physiological requirements. Specifically, in B lymphocytes, these pathways are activated to meet energetic demands in relation to their maturation status and their functional orientation (tolerance, effector or regulatory activities). These metabolic programs are differentially involved depending on the receptors and the co-activation molecules stimulated. Their induction may also vary according to the influence of the microenvironment, i.e. the presence of T cells, cytokines … promoting the expression of particular transcription factors that direct the energetic program and modulate the number of ATP molecule produced. The current review provides recent advances showing the underestimated influence of the metabolic pathways in the control of the B cell physiology, with a particular focus on the regulatory B cells, but also in the oncogenic and autoimmune evolution of the B cells.

Keywords: B lymphocytes; Breg cells; autoimmunity; cancer; metabolism; regulatory activity.

Figure 1

Overview of the metabolic pathways and stimulatory signals in activated B cells. Glucose has a pivotal role in the supply of energy and biomolecules. GLUT1 regulates glucose transport allowing glucose to fuel the glycolytic pathway and the TCA cycle within the mitochondria. The TCA cycle produces NADH and FADH2, which deliver electrons flux to the Electron Transport Chain for ATP generation during the oxidative phosphorylation. B cell metabolism can shunt from these pathways toward the pentose phosphate pathway (PPP) to increase nucleotide biosynthesis. In activated B cells, the high flux of glucose grants the biomolecules required for the cell expansion. Because of that, there is a large production of lactate and increased lipid synthesis. Fatty acid oxidation and glutaminolysis reactions are also increased to sustain the TCA cycle and replace the intermediates consumed in other biological processes. Stimulatory signals from the BCR and TLRs or from CD40 or BAFFR co-stimulatory molecules activate intra-cellular pathways with the recruitment of transcription factors leading to the transcription of glycolysis genes in the nucleus. The induction of the metabolic programs is under the control of numerous transcription factors, miRNA and enzymes that have positive (pointed arrow) or inhibitory (flattened arrow) effects. Only intermediates, transcription factors, enzymes and signaling molecules mentioned in the review are shown. α-KG, α-ketoglutarate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; BCR, B cell receptor; F1,6BP, Fructose 1,6-bisphosphate; F2,6BP, Fructose 2,6-bisphosphate; F6P, Fructose 6-phosphate; G6P, Glucose 6-phosphate; G6PD, Glucose-6-phosphate dehydrogenase; GPI1, glucose-6-phosphate isomerase; 6PGL, 6-Phosphogluconolactonase; GSK3, glycogen synthase kinase 3; HK2, Hexokinase 2; LDHA, lactate dehydrogenase A chain; OXPHOS, Oxidative phosphorylation; PEP, Phosphoenolpyruvate; PFK1, Phosphofructokinase 1; PFK2, Phosphofructokinase 2; PP2A, Protein phosphatase 2; TLR, Toll-like receptor.

Figure 2

Survey of metabolic programs in Breg cells. Metabolic and regulatory programs share common signaling cascades in B cells developing regulatory properties. Activation signals from the BCR and TLR9 induce different intracellular pathways triggering HIF-1α a key player that govern transcription of the prototypic regulatory cytokine IL-10 gene and genes involved in the metabolic programs into the nucleus. The polarization into Breg cells is under the control of a number of transcription factors and enzymes having positive (pointed arrow) or inhibitory (flattened arrow) effects. Glycolysis has a central role to generate energy and biomolecules. Through the GLUT1 transporter, glucose fuels the TCA cycle within the mitochondria. During the TCA cycle, energy is generated through oxidative phosphorylation and fatty acid oxidation brings additional substrates to the TCA cycle and increases lipid synthesis. One intermediate of this pathway, the GGPP molecule produced during cholesterol metabolism induces Blimp1 another key transcription factor of the Breg program following TLR9 stimulation leading to enhanced IL-10 production. The co-stimulatory CD40 molecule can also stimulates HIF-1α to circumvent the BCR-dependent cascade and contributes to the Breg polarization. α-KG, α-ketoglutarate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; BCR, B cell receptor; GGPP, geranylgeranyl pyrophosphate; GSK3, glycogen synthase kinase 3; OXPHOS, Oxidative phosphorylation; STIM, stromal interaction molecule; TLR, Toll-like receptor.