Metabolic Checkpoints in Differentiation of Helper T Cells in Tissue Inflammation

Abstract

Naïve CD4+ T cell differentiate into effector and regulatory subsets of helper T (Th) cells in various pathophysiological conditions and modulate tissue inflammation in autoimmune diseases. While cytokines play a key role in determining the fate of Th cells differentiation, metabolites, and metabolic pathways profoundly influence Th cells fate and their functions. Emerging literature suggests that interplay between metabolic pathways and cytokines potentiates T cell differentiation and functions in tissue inflammation in autoimmune diseases. Metabolic pathways, which are essential for the differentiation and functions of Th cell subsets, are regulated by cytokines, nutrients, growth factors, local oxygen levels, co-activation receptors, and metabolites. Dysregulation of metabolic pathways not only alters metabolic regulators in Th cells but also affect the outcome of tissue inflammation in autoimmune and allergic diseases. Understanding the modulation of metabolic pathways during T cells differentiation may potentially lead to a therapeutic strategy for immune-modulation of autoimmune and allergic diseases. In this review, we summarize the role of metabolic checkpoints and their crosstalk with different master transcription factors and signaling molecules in differentiation and function of Th subsets, which may potentially unravel novel therapeutic interventions for tissue inflammation and autoimmune disorders.

ATP Triggers Human Th9 Cell Differentiation via Nitric Oxide-Mediated mTOR-HIF1α Pathway

“…T cells activation and differentiation relies on aerobic glycolysis, instead of oxidative phosphorylation, in order to meet their increased biosynthetic energy demands (24–26). As a result of glycolysis and metabolic activities, lactate accumulate upon T cell activation (24, 27, 28). To understand the metabolic requirements during human Th9 cells differentiation, we measured the lactate production in effector subsets of human Th cells.…”

“…In fact, Th2, Th9, and Th17 cells, which produce IL-9, also produce higher amounts of lactate as compared to non-IL-9-producing Th0 and Th1 cells (Figure 1A). Since glycolysis leads to lactate production coupled with ATP generation (24, 29, 30), therefore we tested whether Th9 cells also generate higher levels of ATP to support the energy demands of Th9 cells. As compared to Th0, Th9 cells generate significantly higher amounts of ATP (Figure 1B), which led us to hypothesize whether ATP contributes to the differentiation of human Th9 cells.…”

“…The role of NO was tested in T cells differentiation, as NO was found to suppress IL-17 while it promotes IL-9 in Th17 cells (22, 34). Furthermore, the role of NO was also found to directly influence IL-9 induction in Th9 cells, as NOS2 deficiency was found to attenuate IL-9 induction and differentiation of Th9 cells (22, 24). It was shown that ATP contribute to the generation of NO production (35).…”

“…It is demonstrated that mTOR signaling leads to HIF-1α activation, which play critical role in differentiation and interplay between effector and regulatory T cells (24, 38, 39). Our data indicated that eATP-NO-mTOR axis is essential in production of IL-9 in human Th9 cells.…”

“…Under physiological conditions, cellular ATP is released into extracellular milieu, and therefore activates purinergic receptors signaling upon its binding to P2X and P2Y surface receptors. The role of ATP was found to be associated with Th17 cells differentiation, as ATP found to enhance the expression of TGF-β, IL-6, IL-23p19, and thus enhanced Th17 cell generation and exacerbated T-cell-mediated colitis in mouse model (23, 24). Similar to Th17 cells, we have shown here that eATP signals through purinergic receptors and enhances the human Th9 cells differentiation.…”