Metabolic Pathways Involved in Regulatory T Cell Functionality

Rosalie W M Kempkes, Irma Joosten, Hans J P M Koenen, Xuehui He, Rosalie W M Kempkes, Irma Joosten, Hans J P M Koenen, Xuehui He

Abstract

Regulatory T cells (Treg) are well-known for their immune regulatory potential and are essential for maintaining immune homeostasis. The rationale of Treg-based immunotherapy for treating autoimmunity and transplant rejection is to tip the immune balance of effector T cell-mediated immune activation and Treg-mediated immune inhibition in favor of Treg cells, either through endogenous Treg expansion strategies or adoptive transfer of ex vivo expanded Treg. Compelling evidence indicates that Treg show properties of phenotypic heterogeneity and instability, which has caused considerable debate in the field regarding their correct use. Consequently, for further optimization of Treg-based immunotherapy, it is vital to further our understanding of Treg proliferative, migratory, and suppressive behavior. It is increasingly appreciated that the functional profile of immune cells is highly dependent on their metabolic state. Although the metabolic profiles of effector T cells are progressively understood, little is known on Treg in this respect. The objective of this review is to outline the current knowledge of human Treg metabolic profiles associated with the regulation of Treg functionality. As such information on human Treg is still limited, where information was lacking, we included insightful findings from mouse studies. To assess the available evidence on metabolic pathways involved in Treg functionality, PubMed, and Embase were searched for articles in English indexed before April 28th, 2019 using "regulatory T lymphocyte," "cell metabolism," "cell proliferation," "migration," "suppressor function," and related search terms. Removal of duplicates and search of the references was performed manually. We discerned that while glycolysis fuels the biosynthetic and bioenergetic needs necessary for proliferation and migration of human Treg, suppressive capacity is mainly maintained by oxidative metabolism. Based on the knowledge of metabolic differences between Treg and non-Treg cells, we additionally discuss and propose ways of how human Treg metabolism could be exploited for the betterment of tolerance-inducing therapies.

Keywords: FOXP3; human Treg cells; metabolism; migration; proliferation; suppressive function; tolerance-inducing therapies.

Copyright © 2019 Kempkes, Joosten, Koenen and He.

Figures

Figure 1
Figure 1
Immunosuppressive mechanisms underlying Treg-mediated immune suppression. Treg are characterized by expression of the cell surface markers CD4+, CD25high and CD127low/−, and transcription factor FOXP3. Treg modulate the immune system using their suppressive molecules PD-1, CTLA-4, CD39, and various surface receptors through inhibition of dendritic cell (DC) function and maturation, through the secretion of anti-inflammatory cytokines such as IL-10, TGF-β and IL-35, and/or through direct inhibition of Teff via induction of cytolysis using granzyme and metabolic disruption. Moreover, Treg can reduce Teff activation by limiting TCR-ligand binding.
Figure 2
Figure 2
Overview of cellular metabolism in T cells. The first step of glycolysis is the conversion of glucose into glucose-6-phosphate by hexokinases (HK) or glucokinase (GCK). During glycolysis, glucose can be shuttled away toward the pentose phosphate pathway (PPP), or stay in glycolysis resulting in its conversion into pyruvate. Pyruvate can either be converted to lactate by lactate dehydrogenase (LDH), using the nicotinamide adenine dinucleotide (NADH) produced during glycolysis, or it can be converted into acetyl-CoA and enter the tricarboxylic acid (TCA) cycle. The TCA cycle can also be fueled by acetyl-CoA produced during FAO and α-ketoglutarate following glutaminolysis. Subsequently, the TCA cycle fuels OXPHOS and FAS. NADH and reduced nicotinamide adenine dinucleotide phosphate (NADPH) are produced during the conversion of various metabolites and play an important role in proton homeostasis and ROS production via the NADP+ complex and glutathione metabolism. Although all these metabolic pathways are interlinked, cells can regulate their isolated activity and compensate for alterations in the different pathways. The PI3K-Akt-mTOR pathway plays a role in metabolic regulation through various routes. Glycolysis is stimulated via Akt and HIF-1α while fatty acid synthesis and amino acid synthesis are impacted by and impact mTORC1. The PI3K-Akt pathway also modulates FOXP3 expression, which itself impact metabolism via Myc and Akt signaling. OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation; FAS, fatty acid synthesis.
Figure 3
Figure 3
Summary of metabolic pathways involved in distinct Treg functionalities. Treg have distinct metabolic phenotypes throughout their different phases, although many pathways remain to be elucidated. (A) During proliferation, Treg have increased glycolysis and FAO. Deficiency of glutamine and tryptophan steers T cells toward Treg differentiation (–31). (B) To support the increased need for energy during migration, Treg increase their glycolytic flux. Metabolic shifts in other pathways have not been described for Treg migration (, , –39). (C) Treg show decreased glycolysis and increased OXPHOS, FAO, FAS and tryptophan metabolism during their phase of suppressive function. No relevance for the TCA cycle has been reported (, , –, , , , , , –53). The blue and red arrows are indicative for increased or decreased activity of the specific pathway in the functional phenotype of Treg, respectively. FAO, fatty acid oxidation; FAS, fatty acid synthesis; TCA, tricarboxylic acid; OXPHOS, oxidative phosphorylation.

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