The interplay between regulatory T cells and metabolism in immune regulation

Abstract

Regulatory T cells (Tregs) are crucial for peripheral tolerance and are intimately involved in immunological diseases and cancer. Recent studies have highlighted a key role for Tregs in metabolic disorders, for instance as they accumulate in the adipose tissue to protect against obesity-related inflammation and insulin resistance. Conversely, the generation and immunosuppressive functions of Tregs are influenced by both systemic and cellular metabolism. The nutritional status as well as metabolic cues such as those provided by leptin impinge upon the proliferation of Tregs. In addition, the mTOR-dependent lipid metabolism has a crucial role in programming the activity of Tregs under steady-state conditions as well as upon activation. This review discusses the intricate interaction between Tregs and metabolism, focusing on the roles of Tregs in systemic and local metabolic circuitries as well as on the regulation of Treg abundance and function by metabolic signals.

Keywords: FOXP3; Treg; lipid metabolism; mTOR; metabolism.

Figure 1. Impact of metabolism and mTOR signaling on the abundance and immunosuppressive activity of regulatory T cells. The T-cell receptor (TCR) and interleukin-2 (IL-2) receptor transduce two major immune inputs that activate the mTOR complex 1 (mTORC1), which promotes cholesterol/lipid biosynthesis. In particular, the mevalonate pathway stimulates the proliferation of regulatory T cells (Tregs) and the expression of effector molecules on their surface, hence establishing their functional competence. mTORC1 also negatively regulates the activity of mTORC2 to modulate Treg function. The leptin-dependent activation of mTOR maintains the anergic status of Tregs through an unknown mechanism. Blocking the leptin receptor (OBR) or reducing the levels of leptin enhances Treg proliferation in vitro and in vivo. Amino acids also activate mTOR, which limits the generation of inducible Tregs (iTregs) through an undefined mechanism. Tregs preferentially accumulate in the visceral adipose tissue (VAT), where they exhibit increased peroxisome proliferator-activated receptor γ (PPARγ) expression levels. The activation of PPARγ by either endogenous ligands or exogenous agonists stimulates fatty acid metabolism, hence promoting Treg proliferation as well as the expression of GATA-binding protein 3 (GATA3) and forkhead box P3 (FOXP3), which sustain the immunosuppressive activity of these cells.