Regulation of Immune Cell Functions by Metabolic Reprogramming

Abstract

Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

“…Included in this group are GAPDH, ENO1, PKM, LDHA and GPI. In T cells, during high glycolytic flux, GAPDH has been shown to induce translation of IFNg and IL-2 while it's interaction with Rheb is inhibited, releasing Rheb to activate mTORC1 40,42 . Similarly, PKM2, one of two transcripts of PKM, can activate mTORC1 by phosphorylating another inhibitor AKT1S1, which could account for increased mTORC1 activation in rapidly cycling cells 43 .…”

Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8 + T cell stemness and antitumor immunity

“…IL-2 | IL-21 | LDH | adoptive immunotherapy | immunometabolism I mmune responses are initiated by engagement of the T cell receptor (TCR) and then critically controlled by cytokines, which influence differentiation, proliferation, and survival. Altering metabolic pathways can affect the actions of immune cells (1)(2)(3)(4), and different cellular subtypes vary in how they produce and expend energy (5). For example, naïve T cells are quiescent, with a low energy demand that is met primarily via oxidative phosphorylation, but after TCR activation, T cells markedly increase their metabolic activity, acutely engaging in aerobic glycolysis and later also up-regulating oxidative ATP production (6), with production of a range of cytokines.…”

Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling

“…In the tumor microenvironment (TME), the tumor-suppressive function of resident immune cells, such as macrophages and T cells, are switched to pro-tumoral functions [121]. The anergic T cells and tumor-infiltrating T cells are reported to exhibit similar properties, such as enhanced DGKα levels, attenuated ERK responses (both low basal phosphorylation of ERK and low stimulation-induced phosphorylation of ERK and c-JNK), and downregulated expression of AKT and AKT client proteins (two regulatory factors of NF-κB: IκB and GSK3) [122].…”