Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation

Abstract

The immune system is necessary for protecting against various pathogens. However, under certain circumstances, self-reactive immune cells can drive autoimmunity, like that exhibited in type 1 diabetes (T1D). CD4+ T cells are major contributors to the immunopathology in T1D, and in order to drive optimal T cell activation, third signal reactive oxygen species (ROS) must be present. However, the role ROS play in mediating this process remains to be further understood. Recently, cellular metabolic programs have been shown to dictate the function and fate of immune cells, including CD4+ T cells. During activation, CD4+ T cells must transition metabolically from oxidative phosphorylation to aerobic glycolysis to support proliferation and effector function. As ROS are capable of modulating cellular metabolism in other models, we sought to understand if blocking ROS also regulates CD4+ T cell activation and effector function by modulating T cell metabolism. To do so, we utilized an ROS scavenging and potent antioxidant manganese metalloporphyrin (MnP). Our results demonstrate that redox modulation during activation regulates the mTOR/AMPK axis by maintaining AMPK activation, resulting in diminished mTOR activation and reduced transition to aerobic glycolysis in diabetogenic splenocytes. These results correlated with decreased Myc and Glut1 upregulation, reduced glucose uptake, and diminished lactate production. In an adoptive transfer model of T1D, animals treated with MnP demonstrated delayed diabetes progression, concurrent with reduced CD4+ T cell activation. Our results demonstrate that ROS are required for driving and sustaining T cell activation-induced metabolic reprogramming, and further support ROS as a target to minimize aberrant immune responses in autoimmunity.

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

“…42,53 Previous studies demonstrated that ROS further activates Akt/mTOR pathway, enabling optimal T-cell proliferation and glycolysis. [53][54][55] Therefore, our results confirm that the inhibition of ROS production and the blockade of mTOR signalling by alum in PM-acti- The ratio of serum IgG1/IgG2a is significantly higher in mice immunized with PM plus alum, indicating that alum also impairs in vivo tolerogenic responses to PM. Remarkably, alum did not enhance the capacity of PM to induce allergen-specific antibodies with blocking activity, indicating that the absence of alum in PM vaccine formulations would not significantly modify this feature.…”

Enzyme Profile of Peripheral Blood Lymphocytes in Patients With the Renal Cell Carcinoma Before and After Surgical Treatment

“…Компенсировать недостаточность анаэробно-го гликолиза может перенос продуктов липидно-го катаболизма через Г3ФДГ на окислительно-восстановительные реакции гликолиза [19,21]. Однако повышение активности Г3ФДГ в лим-фоцитах больных ПКР наблюдается только на 14 сутки после оперативного вмешательства.…”

Regulation of redox balance in cancer and T cells

“…MYC is an essential transcription factor in activated T cells that upregulates glycolysis and mitochondrial metabolism to generate the biosynthetic intermediates and adenosine triphosphate (ATP) needed for cell growth and proliferation (82). A negative regulator of MYC, AMP-activated protein kinase (AMPK), has been found to be inhibited by ROS post-TCR engagement (83). Therefore, ROS potentially amplify the MYC signaling pathway, inducing the metabolic shift, thus the antigen-stimulated T cell expansion.…”