Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

Abstract

Regulatory T (Treg) cells are crucial for peripheral immune tolerance and prevention of autoimmunity and tissue damage. Treg cells are inherently defined by the expression of the transcription factor Foxp3, which enforces lineage development and immune suppressive function of these cells. Under various conditions as observed in autoimmunity, cancer and non-lymphoid tissues, a proportion of Treg cells respond to specific environmental signals and display altered stability, plasticity and tissue-specific heterogeneity, which further shape their context-dependent suppressive functions. Recent studies have revealed that metabolic programs play pivotal roles in controlling these processes in Treg cells, thereby considerably expanding our understanding of Treg cell biology. Here we summarize these recent advances that highlight how cell-extrinsic factors, such as nutrients, vitamins and metabolites, and cell-intrinsic metabolic programs, orchestrate Treg cell stability, plasticity, and tissue-specific heterogeneity. Understanding metabolic regulation of Treg cells should provide new insight into immune homeostasis and disease, with important therapeutic implications for autoimmunity, cancer, and other immune-mediated disorders.

Expression of Tim-3 drives naïve Treg to an effector-like state with enhanced suppressive activity

“…There is now an extensive literature demonstrating the roles of shifts in metabolic pathways among different subsets of T cells and during transitions between different activation and effector states of these same cells. For example, Treg appear to rely predominantly on mitochondrial metabolism, including lipid oxidation, while actively suppressing glycolysis, in a FoxP3-dependent manner (Shi and Chi, 2019). Thus, the upregulation of glycolysis genes, along with downregulation of oxidative phosphorylation genes, in Tim3-expressing Treg may be due at least in part to the downregulation of FoxP3.…”

“…Transient destabilization of Treg is thought to be important for licensing efficient effector T cell responses to pathogens, while aberrant or more profound Treg destabilization can lead to autoimmunity (Piconese and Barnaba, 2015;Sakaguchi et al, 2013;Shi and Chi, 2019). We therefore were interested in determining whether transgenic expression of Tim-3 altered Treg homeostasis in vivo.…”

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

“…Under normal homeostatic conditions, where FoxP3 expression is maintained, the majority of Tregs are stable in phenotype and function. However, this stability depends on each cell's ability to prevent disruption of FoxP3 expression and the acquisition of an inflammatory effector function [10,19]. In the context of pathologies, changes in nutrient availability or alterations to genes associated with metabolic regulation can affect Treg stability and function [20–22].…”

“…During tumorigenesis, free FA are released from more complex lipids, altering the FA composition of the TME [127]. Tregs in this setting express high levels of the FA transporters CD36 and SLC27A1, which allow these cells access to additional energetic sources to fuel FA metabolism [10,128]. This exploitation of FA by Tregs in the TME provides the Tregs with the nutrients they need to survive and be fully functional, resulting in the barring of Teffs from attacking cancer cells.…”

“…Mutations in this gene result in severe immune dysregulation and initiate the autoimmune (AI) disease polyendocrinopahthy enteropathy X‐linked (IPEX) syndrome in humans as well as a severe, spontaneous autoimmune disorder in mice [8]. Tregs also express the α‐subunit of the IL‐2 receptor (CD25) and require constitutive IL‐2 signaling to maintain their homeostasis and function [9,10]. The loss of CD25 in Tregs abrogates Treg development and FoxP3 expression, but not in mature Treg [11,12].…”