Immune Metabolism of IL-4-Activated B Cells and Th2 Cells in the Context of Allergic Diseases

Abstract

Over the last decades, the frequency of allergic disorders has steadily increased. Immunologically, allergies are caused by abnormal immune responses directed against otherwise harmless antigens derived from our environment. Two of the main cell types driving allergic sensitization and inflammation are IgE-producing plasma cells and Th2 cells. The acute activation of T and B cells, their differentiation into effector cells, as well as the formation of immunological memory are paralleled by distinct changes in cellular metabolism. Understanding the functional consequences of these metabolic changes is the focus of a new research field termed "immune metabolism". Currently, the contribution of metabolic changes in T and B cells to either the development or maintenance of allergies is not completely understood. Therefore, this mini review will introduce the fundamentals of energy metabolism, its connection to immune metabolism, and subsequently focus on the metabolic phenotypes of IL-4-activated B cells and Th2 cells.

Keywords: Warburg metabolism; allergies; fatty acid oxidation (FAO); glycolysis; immune metabolism; metabolism; oxidative phosphorylation.

Figure 1

Cellular metabolism under steady-state conditions and metabolic changes associated with cancer cells, proliferating cells, or activated immune cells. Under steady-state conditions (A), cells take up glucose from their medium and metabolize it to pyruvate in a cytoplasmic process called glycolysis. Pyruvate is subsequently imported into the mitochondria, where it is used in the Krebs cycle to generate the reduction equivalents NADH and FADH₂. Besides glucose, the Krebs cycle can also be replenished by acetyl-CoA derived from fatty acid oxidation (FAO) or glutamate derived from amino acid metabolism. NADH and FADH₂ generated in the Krebs cycle are then used in the oxidative phosphorylation to generate energy (B). Here oxygen is used as the terminal electron acceptor in the electron transport chain (consisting of complexes I through IV) to generate a proton gradient over the inner mitochondrial membrane (measured as oxygen consumption rate (OCR)). This proton gradient drives the generation of ATP via the ATP-synthase complex. Under certain conditions, cancer cells, strongly proliferating cells, or activated immune cells switch their metabolism to predominantly produce lactate from glucose instead of fully oxidizing glucose into CO₂ in the mitochondrion (C). The produced lactate is secreted from the cell, leading to an extracellular pH decrease that can be measured as extracellular acidification rate (ECAR). Moreover, the lack of pyruvate results in a “disrupted” Krebs cycle, which the activated immune cells use to generate important biosynthetic intermediates needed for immune cell effector function such as prostaglandins, NO, ROS, or itaconate. Additionally, fumarate and acetyl-CoA (generated, for example, from citrate via the ATP-citrate lyase, ACL) can be used for epigenetic modification. For more information see main text. FAO, fatty acid oxidation; ROS, reactive oxygen species; NO, nitric oxide; FAS, fatty acid synthesis; PDH, pyruvate dehydrogenase; ACL, ATP-citrate lyase; GDH, glutamate dehydrogenase; IDH, isocitrate dehydrogenase; IRG1, immune-responsive gene 1; HIF-1a, hypoxia-inducible factor 1a; OCR, oxygen consumption rate; ECAR, extracellular acidification rate; I to IV, complex I to IV.

Figure 2

Metabolic phenotype and main signaling pathways associated with the activation of T and B cells in allergies. Cell types are grouped within the metabolic pathways (glycolysis, oxidative phosphorylation (OxPhos), fatty acid oxidation (FAO)) according to the published and discussed literature (A). Upon activation, IL-4-stimulated B cells undergo complex metabolic changes, including a poly ADP-ribose polymerase 14 (PARP14)-dependent increase in glucose consumption driving both nucleotide synthesis and IgG1 production as well as high rates of OxPhos and glutamine metabolism, which promote B cell activation, plasmablast differentiation, and isotype switching (B). In naïve CD4⁺ T cells antigen-dependent stimulation results in a mechanistic target of rapamycin (mTOR)-dependent T helper cell differentiation. While inhibition of mTOR results in differentiation of regulatory T cells (Treg) with a predominant carnitine palmitoyl transferase 1a (CPT1a)-dependent increase in FAO, mTOR activation is critically important for either Th1, Th2, Th17 differentiation. In both Th1 and Th17 cells, mTOR activation drives a glycolytic phenotype. In Th2 cells, mTOR complex 2 (mTORC2) promotes a RhoA-dependent increase in glycolysis (which was shown to contribute to IL-5 and IL-13 production) and an increase in mitochondrial oxygen consumption (whose contribution to Th2 effector function is currently unclear). Moreover, activation of mTORC1 and peroxisome proliferator-activated receptor gamma (PPAR-γ) in Th2 cells promotes fatty acid uptake and oxidation which fuels Th2 cell survival, proliferation, and effector function (C). In germinal centers (GC), follicular T helper cells (TFH) HIF-1/2a-dependently promote the activation of germinal center B cells via CD154-dependent co-stimulation and the production of the switching cytokines IL-4 and IL-21 (D). Here, TFH cells display both enhanced glycolysis and OxPhos while using the lipid metabolism enzyme stearoyl-CoA desaturase (SCD) to reduce ER stress and increase survival. In contrast to other cells types, antigen-activated GC B cells mainly rely on FAO for energy generation while suppressing glycolytic genes. For more detailed information see text. OxPhos, oxidative phosphorylation; FAO, fatty acid oxidation; BCR, B cell receptor; LPS, lipopolysaccharide; Glut1, glucose transporter 1; TCR, T cell receptor; 2-DG, 2-deoxy glucose; mTOR(C1/2), mechanistic target of rapamycin complex 1/2; PDH(K1), pyruvate dehydrogenase (kinase 1); LDH, lactate dehydrogenase; Treg, regulatory T cell; CPT1a/2, carnitine palmitoyl transferase 1a/2; PARP14, Poly ADP-ribose polymerase 14; PPAR-γ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; STAT6, signal transducer and activator of transcription 6; NOX2, NADPH oxidase 2; BCL-6, B-cell lymphoma 6 protein; GC, germinal center; TFH cell, follicular T helper cell; SCD, stearoyl-CoA desaturase; HIF-1/2a, hypoxia inducible factor 1/2a.