Immunometabolic Regulation of Interleukin-17-Producing T Helper Cells: Uncoupling New Targets for Autoimmunity

Abstract

Interleukin-17-producing T helper (Th17) cells are critical for the host defense of bacterial and fungal pathogens and also play a major role in driving pathogenic autoimmune responses. Recent studies have indicated that the generation of Th17 cells from naïve CD4⁺ T cells is coupled with massive cellular metabolic adaptations, necessary to cope with different energy and metabolite requirements associated with switching from a resting to proliferative state. Furthermore, Th17 cells have to secure these metabolic adaptations when facing nutrient-limiting environments, such as at the sites of inflammation. Accumulating data indicates that this metabolic reprogramming is significantly linked to the differentiation of T helper cells and, particularly, that the metabolic changes of Th17 cells and anti-inflammatory Forkhead box P3⁺ regulatory T cells are tightly and reciprocally regulated. Thus, a better understanding of these processes could offer potential new targets for therapeutic interventions for autoimmune diseases. In this mini-review, we will highlight some of the recent advances and discoveries in the field, with a particular focus on metabolic demands of Th17 cells and their implications for autoimmunity.

Keywords: autoimmune diseases; glycolysis; immunometabolism; interleukin-17-producing T helper cells; oxidative phosphorylation; regulatory T cells.

Figure 1

Interleukin-17-producing T helper (Th17) cells and regulatory T cells (Tregs) have distinct metabolic requirements. The presentation of antigen and costimulation by dendritic cells induce the reprogramming of T cells into an aerobic glycolytic “Warburg” metabolism, characterized by the increased expression of glucose transporter 1 (Glut1) and augmented glucose uptake. Generally, in the presence of transforming growth factor (TGF)-β with the combination of other cytokines such as interleukin (IL)-6, activated T cells are polarized into specialized Th17 cells, which have an even further enhanced glycolytic metabolism and flux into intermediate pathways, required for the generation of amino acids, nucleotides, and fatty acids essential for Th17 effector function. Conversely, the induction of Tregs from activated T cells by TGF-β and the combination of other cytokines, such as IL-2, results in an increased uptake of fatty acids (FA) and an elevated lipid and mitochondrial oxidative metabolism. Within each subset, there exists further heterogeneity, depending on the presence of further local stimulatory cues, such as other cytokines and small metabolites, thus generating pathogenic or non-pathogenic Th17 cells and various polarized regulatory Treg cells; all of which exhibit further metabolic complexity. Th17 cells are dependent on aerobic glycolytic metabolism, as inhibiting glycolysis with 2-deoxyglucose (2-DG) or dichloroacetate (DCA) prevents Th17 cell generation even in the presence of Th17 cell-promoting conditions. Likewise, the addition of exogenous fatty acids or soraphen A (SorA), which enhances lipid oxidative metabolism, similarly inhibits Th17 cell generation. These metabolic interventions have the opposite effect on the generation of Tregs, which are conversely enhanced by treatments that augment lipid oxidative metabolism and blunted by inhibitors of lipid transport such as etomoxir. Cholesterol derivatives are essential for Th17 cell differentiation and blockade of cholesterol biosynthesis, for example, with ketoconazole, inhibits the generation of Th17 cells but has no effect on Tregs.