Metabolic control of type 2 immunity

Abstract

Type 2 immune responses play key roles in protection against parasitic worm infections, whole-body metabolic homeostasis, wound healing, and the development of allergies. As a result, there is considerable interest in understanding the pathways that regulate type 2 immunity in order to identify strategies of targeting and controlling these responses. In recent years, it has become increasingly clear that the functional properties of immune cells, including those involved in type 2 immune responses, are dependent on the engagement of specific metabolic pathways such as aerobic glycolysis and fatty acid oxidation (FAO). We here discuss the latest insights in the metabolic regulation of immune cells that initiate type 2 immune responses, such as dendritic cells and innate lymphoid cells, as well as immune cells involved in the effector phase, like T helper 2 (Th2) cells, B cells and alternatively activated macrophages (M2 macrophages). Finally, we consider whether these findings may provide new prospects for the treatment of type 2 immune response-associated diseases.Keywords: Cellular metabolism r Glycolysis r M2 macrophage r Oxidative phosphorylation r Th2 response r Type 2 immunity IntroductionType 2 immune responses are initiated by dendritic cells (DCs) that promote the differentiation of naïve CD4+ T cells towards a T helper 2 (Th2) phenotype, which is characterized by the production of the prototypical type 2 cytokines: interleukin-4 (IL-4), . In some settings, type 2 innate lymphoid cells (ILC2s) and basophils contribute to this process by also presenting antigens to naïve T cells and by producing type 2 cytokines. IL-4, IL-5, and IL-13 play a central role in driving the humoral and cellular arms of type 2 immunity. IL-4 released in B-cell follicles by a specialized subset of Th2 cells, termed T follicular helper (Tfh) cells, promotes B cells to induce antibody class switching towards immunoglobulin E (IgE) as well as toward IgG4 in humans and IgG1 in mice [2]. Local release of IL-5 at the site of inflammation leads to the recruitment and activation of eosinophils which, similar to basophils and mast cells, release preformed granules with toxic proteins, histamine, and other vasoactive amines upon engagement of their high-affinity IgE receptorsCorrespondence: Dr. Bart Everts e-mail: b.everts@lumc.nl (FC epsilon receptor [FcεR]) by immune complexes of IgE [1]. In addition, these granulocytes produce bio-active lipids such as leukotrienes and prostaglandins, and a wide variety of cytokines. Finally, local release of both IL-4 and IL-13 induces the alternative activation of macrophages (M2 macrophages), a subset of macrophages that is known to assist in the killing of parasites, resolution of inflammation and repair of any tissue damage that has occurred [3]. However, these responses are also the main driver of allergic reactions that result in diseases such as asthma, rhinitis, and atopic dermatitis [1]. Given the vital contributions of each of these cells in the outcome of type 2 immune response-associated d...

The Influence of Dietary Fatty Acids on Immune Responses

“…ILCs significantly contribute to the homeostasis of adipose tissues [168]. The effects of dietary nutrients, such as tryptophan metabolites, vitamin A and retinoic acid, on ILCs population, have been widely investigated [168,[170][171][172][173]. Due to the expression of lipid receptors, ILCs possess the potential to respond to dietary FAs [174,175].…”

Shaping the diversity of Th2 cell responses in epithelial tissues and its potential for allergy treatment

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Early-life undernutrition reprograms CD4+ T-cell glycolysis and epigenetics to facilitate asthma

“…Simultaneously, 2-DG treatment reduced T H 2 cytokine expression in lung tissue and BALF ( Fig 6, I and J) and ameliorated the aggravated T H 2 cell responses in PRD mice, which is consistent with previous reports that 2-DG could inhibit glycolysis within T cells to alleviate experimental asthma. 14,20,33 Except for T H 2 cells, 2-DG could also target M2 macrophages to alleviate experimental asthma. 51 Therefore inhibition of M2 macrophage polarization by 2-DG administration might contribute to amelioration of early-life malnutritionexacerbated experimental asthma.…”

“…19 Compared with T H 1 and T H 17 cells, T H 2 cells show stronger glycolytic rates. 14,20,21 Therefore the characterization of effects of early-life undernutrition on T cells and especially on metabolic changes within T cells is central to our understanding of the developmental asthma in offspring under conditions of maternal malnutrition.…”