The Therapeutic Potential of T Cell Metabolism

Abstract

Transplant rejection mediated by the adaptive immune system remains a major barrier to achieving long-term tolerance and graft survival. Emerging evidence indicates that lymphocytes rapidly shift their metabolic programs in response to activation, co-stimulatory, and cytokine signals to support required effector cell differentiation and function. These observations have led to the hypothesis that manipulating the metabolic programs of immune cells could serve as a powerful therapeutic strategy for attenuating deleterious immune responses and facilitating durable tolerance in the setting of allogeneic solid organ or bone marrow transplant. In this mini-review, we introduce the fundamentals of metabolism, highlight the current understanding of how adaptive immune cells utilize their metabolic programs, and discuss the potential for targeting metabolism as a therapeutic approach to induce tolerance in the transplant setting.

Metformin use in the first year after kidney transplant, correlates, and associated outcomes in diabetic transplant recipients: A retrospective analysis of integrated registry and pharmacy claims data

“…via AMPK-mTOR-STAT3 signaling 48 and T cell regulation. 49 Again, our study does not support definitive conclusions for effects on allograft health, but the absence of increased risk is reassuring for the overall safety profile.…”

“…Potential mechanisms of allograft protection would include the ability of metformin to reduce kidney injury, possibly through AMPK activation 46,47 and its anti-inflammatory and immune modulatory effects (eg, via AMPK-mTOR-STAT3 signaling 48 and T-cell regulation). 49 Again, our study does not support definitive conclusions for effects on allograft health, but the absence of increased risk is reassuring for the overall safety profile.…”

Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis

“…Metabolic reprogramming refers to changes in bioenergetic pathways in activated immune cells. Some of the key metabolic cascades that are modulated include glycolysis, oxidative phosphorylation, the pentose phosphate pathway, fatty acid oxidation and amino acid metabolism [1,2]. In particular, aerobic glycolysis has been shown to be induced in a variety of activated immune cells such as NK cells, dendritic cells, B cells and effector T cells [1], which in turn modulate their functional characteristics.…”

“…In particular, aerobic glycolysis has been shown to be induced in a variety of activated immune cells such as NK cells, dendritic cells, B cells and effector T cells [1], which in turn modulate their functional characteristics. Notably, the paradigm that metabolic changes may contribute to the functionality of immune cells may open new options for therapeutic interventions in inflammatory diseases [2,3].…”

HDAC1 disrupts the tricarboxylic acid (TCA) cycle through the deacetylation of Nur77 and promotes inflammation in ischemia-reperfusion mice

“…Oxidative phosphorylation and metabolic reprogramming are characteristic of activated inflammatory M1 macrophages [ 29 ]. Glycolysis, oxidative phosphorylation, pentose phosphate pathway, fatty acid oxidation and the metabolism of amino acids represent key metabolic pathways [ 30 , 31 ]. Ischemic preconditioning activates mitochondrial Src, regulating complex I activity and the levels of mitochondrial reactive oxygen species (ROS) to counter myocardial I/R [ 32 ].…”