Metabolic adaptation orchestrates tissue context‐dependent behavior in regulatory T cells

Abstract

Immunological Reviews. 2020;295:126-139. wileyonlinelibrary.com/journal/imr | INTRODUC TI ONThe immune system is mainly responsible for protecting individuals from pathogen invasion. Meanwhile, the immune system also actively participates in tissue repairing and homeostasis, which are critical for the avoidance of autoimmunity. A subset of CD4 + T cells, which is characterized by the expression of the master transcription factor forkhead box protein P3 (Foxp3) and known as regulatory T cells (Tregs), is the major immune subset to maintain the immune homeostasis. 1-4 The importance of Tregs on governing peripheral tissue and immune homeostasis is validated by observations in both human patients and murine models. In humans, the mutations in Foxp3 result in impaired development and dysfunction of Tregs and cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, characterized by multiple autoimmune disorders. 5,6 Mice carrying dysfunctional Foxp3, known as scurfy mice, are deficient in Abstract The diverse distribution and functions of regulatory T cells (Tregs) ensure tissue and immune homeostasis; however, it remains unclear which factors can guide distribution, local differentiation, and tissue context-specific behavior in Tregs. Although the emerging concept that Tregs could re-adjust their transcriptome based on their habitations is supported by recent findings, the underlying mechanisms that reprogram transcriptome in Tregs are unknown. In the past decade, metabolic machineries have been revealed as a new regulatory circuit, known as immunometabolic regulation, to orchestrate activation, differentiation, and functions in a variety of immune cells, including Tregs. Given that systemic and local alterations of nutrient availability and metabolite profile associate with perturbation of Treg abundance and functions, it highlights that immunometabolic regulation may be one of the mechanisms that orchestrate tissue context-specific regulation in Tregs. The understanding on how metabolic program instructs Tregs in peripheral tissues not only represents a critical opportunity to delineate a new avenue in Treg biology but also provides a unique window to harness Treg-targeting approaches for treating cancer and autoimmunity with minimizing side effects. This review will highlight the metabolic features on guiding Treg formation and function in a disease-oriented perspective and aim to pave the foundation for future studies. K E Y W O R D S autoimmunity, cancer, immunometabolism, inflammation, metabolic adaptation, regulatory T cell | 127 WANG et Al.

Immunometabolism: From basic mechanisms to translation

“…More research is necessary to understand the bi‐directional crosstalk between stromal cells and Tregs, commonalities between human and mouse, and the kinetics and phenotype of these cells in obesity and other diseases. Tregs also play key roles to maintain homeostasis in other peripheral tissues including liver, skin, and tumors and are reviewed by Wang et al 74 .…”

Determinants of Tissue-Specific Metabolic Adaptation of T Cells

“…For example, upon entering into the various tissues, T cells can sense nutrient levels present at the site and can then rewire their metabolic activities to a pattern that allows them to survive and function optimally at that site. We refer to these metabolic adjustments made by T cells at tissue-reactive sites as T cell adaptations as was also recently reviewed for Tregs (Wang et al, 2017;Wang et al, 2020b). We propose that 4 factors contribute to the adaptation of T cells to their dynamic tissue environment.…”

Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

“…Further complexity in the area of metabolic control is provided by the unique environmental conditions experienced by Tregs. As a result, tissue-specific Treg subsets have unique metabolic properties [69][70][71]. For example, tissue-resident Tregs incorporate feedback from factors such as hypoxia, which can exert metabolic effects through restriction of OXPHOS and activation of the metabolic regulator hypoxiainducible factor-1α [72][73][74][75]; PPAR-γ, a major regulator of lipid metabolism that enhances exogenous lipid uptake, in visceral adipose tissue Tregs [76]; and bile acid metabolites that enhance mitochondrial ROS production to promote gut iTreg generation [77].…”