Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues

Abstract

Regulator T cells (Tregs) play pivotal roles in maintaining immune tolerance and regulating immune responses against pathogens and tumors. Reprogramming of cellular metabolism has been determined as a crucial process that connects microenvironmental cues and signaling networks to influence homeostasis and function of tissue Tregs. In adaptation to a variety of non-lymphoid tissues, Tregs coordinate local immune signals and signaling networks to rewire cellular metabolic programs to sustain their suppressive function. Altered Treg metabolism in turn shapes Treg activation and function. In light of the advanced understanding of immunometabolism, manipulation of systemic metabolites has been emerging as an attractive strategy aiming to modulate metabolism and function of tissue Tregs and improve the treatment of immune-related diseases. In this review, we summarize key immune signals and metabolic programs involved in the regulation of tissue Tregs, review the mechanisms underlying the differentiation and function of Tregs in various non-lymphoid tissues, and discuss therapeutic intervention of metabolic modulators of tissue Tregs for the treatment of autoimmune diseases and cancer.

Keywords: Treg function; Treg homeostasis; Treg metabolism; metabolic signaling; tissue Treg cells.

Figure 1

Immune signaling pathways involved in the regulation of Treg cell metabolism and adaptation to non-lymphoid tissues. Microenvironmental antigens, co-stimulators, TLRs, and cytokines orchestrate key immune signaling pathways to reprogram cellular metabolism of Tregs in adaptation to non-lymphoid tissues. The PI3K signaling pathway senses the immune signals derived from TCR, co-stimulatory receptors, co-inhibitory receptors, and TLRs, which in turn activates mTOR complexes to orchestrate reprogramming of cellular metabolism via various transcription factors. TCR and co-stimulation activates LKB1 signaling pathway that restricts STAT4 function and promotes stabilization of β-catenin and metabolic reprogramming of Tregs in maintaining immune homeostasis of multiple non-lymphoid tissues. In response to TCR and co-stimulatory signals in the tissue microenvironment, Tregs coordinate a variety of transcription factors that upregulate expression of the genes involved in diverse metabolic programs, including lipid biosynthesis, mitochondrial metabolism, glycolysis, FAO, and AA metabolism. Cytokines existed in various tissues sustain homeostasis and accumulation of tissue Tregs through different transcription factors. VAT-Treg cell accumulation is dependent upon TCR, FOXP3, and IL-33 signaling through activation of GATA3, IRF4, and BATF. IL-7 is required to maintain homeostasis and function of skin-Tregs. TCR, T cell receptor; FAO, fatty acid oxidation; AA, amino acids; VAT, visceral adipose tissue.

Figure 2

Metabolic signaling in the regulation of Treg homeostasis and function. Extracellular and intracellular metabolites regulate Treg homeostasis and function in various non-lymphoid tissues. Reduced production of ATP activates LKB1 signaling pathway that promotes mitochondrial FAO and OXPHOS and mevalonate pathway producing GGPP, which enhances FOXP3 expression and Treg function. Uncontrolled production of mitochondrial ROS induces Treg apoptosis that facilitates tumor immunoevasion. Increased concentration of cellular NAD⁺ enhances function of the deacetylase SIRT1 that destabilizes FOXP3 protein and compromises Treg function. Tregs take up microenvironmental LCFAs and SCFAs via different receptors. FABP5 binds to LCFAs and transfers them to mitochondria in Tregs. Inactivation of FABP5 activates cGAS-STING to promote expression of IL-10 and type I interferons and Treg function. SCFAs suppress activity of HDACs and thereby maintain acetylated FOXP3 and enhance Treg stability. Vitamin D3 metabolite 1,25(OH)₂VD₃-receptor complex binds to VDRE region to enhance Foxp3 gene expression. Distinct amino acids differentially regulate activation of mTOR, which can augment glycolysis to suppress FOXP3 expression via Myc or evoke TFAM function to restrain methylation of CNS2. Activated Tregs elevate uptake of transferrin, which can be converted to reductive iron to facilitate the generation of lipid peroxides. GCLC catalyzes the synthesis of GSH crucial for maintaining cellular redox homeostasis. It functions as a substrate for GPX4 to prevent the accumulation of lipid peroxides in Tregs and subsequent ferroptosis. Ferroptotic Tregs enhance production of pro-inflammatory cytokines such as IL-1β. GGPP, geranylgeranylpyrophosphate; ROS, reactive oxygen species; NAD, nicotinamide adenine dinucleotide; LCFAs, long chain fatty acids; SCFAs, short chain fatty acids; HDAC, histone deacetylase; VDRE, vitamin D response element; CNS2, conserved non-coding sequence 2; GCLC, glutamate cysteine ligase catalytic subunit.