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

Abstract

Regulatory T cells (Tregs) are critical for peripheral immune tolerance and homeostasis, and altered Treg behavior is involved in many pathologies, including autoimmunity and cancer. The expression of the transcription factor FoxP3 in Tregs is fundamental to maintaining their stability and immunosuppressive function. Recent studies have highlighted the crucial role that metabolic reprogramming plays in controlling Treg plasticity, stability, and function. In this review, we summarize how the availability and use of various nutrients and metabolites influence Treg metabolic pathways and activity. We also discuss how Treg‐intrinsic metabolic programs define and shape their differentiation, FoxP3 expression, and suppressive capacity. Lastly, we explore how manipulating the regulation of Treg metabolism might be exploited in different disease settings to achieve novel immunotherapies.

Glucose Metabolism Reprogramming of Regulatory T Cells in Concanavalin A-Induced Hepatitis

“…Teffs are known to utilize glycolysis for survival and effector functions ( Almeida et al, 2021 ). In contrast, Tregs mainly depend on OXPHOS to provide the energy supply needed for stability and inhibitory functions ( Kurniawan et al, 2020 ). Enhanced glycolysis has been reported to correlate with functional impairment of Tregs.…”

Regulatory T cells and transplantation tolerance: Emerging from the darkness?

“…For example, The high expression of CD25 on Treg [17] has raised the possibility that some engineered form of IL‐2 might be used to selectively expand Treg in vivo and enable therapeutic benefit in preclinical studies [78–83]. Distinctive metabolic features of Treg in use of glycolysis, oxidative phosphorylation, and lipid metabolism have also attracted much interest if suitable drug candidates could be identified [84–93]. Potential roles for amino acid metabolism and sensing were initiated by the pioneering work of Munn and Mellor who first identified a role for IDO‐mediated tryptophan catabolism in preventing a maternal immune attack of the allogeneic fetus [11].…”

“…(b) Distinctive metabolic features of Treg in use of glycolysis, oxidative phosphorylation, and lipid metabolism have also attracted much interest if suitable drug candidates could be identified [84][85][86][87][88][89][90][91][92][93].…”

Regulatory T cell targeting in cancer: Emerging strategies in immunotherapy

“…Interaction between CTLA‐4/CD80 or CTLA‐4/CD86 also induces the activity of IDO in DCs, a critical enzyme in the kynurenine pathway that drives the metabolism of the AA tryptophan. Depletion of tryptophan from the TME causes dysfunction and exhaustion of effector T cells, since these cells require tryptophan to carry out their effector functions [5, 7, 19].…”

“…Strategies to indirectly disrupt Treg function have also been investigated including the neutralization of immunosuppressive cytokines produced by Tregs such as IL‐10, IL‐35, and TGF‐β or the blocking of adenosine receptors [22, 24]. The tryptophan depleting enzyme IDO can be targeted to restore the effector function of conventional T cells and skew the TME toward a proinflammatory state [11, 19]. A number of small molecule inhibitors of IDO1, including Epacadostat, have recently entered the clinic, but are demonstrating safety concerns [46].…”