The effect and mechanism of action of PI3K on the Th17/Treg balance may be multifaceted, including promotion of mTOR activity and glucose uptake, mediated by distinct PI3K isoenzymes (64). and maintains their specific characteristics and functions. Treg cells inhibit na?ve T cell activation and prevent the excessive functioning of effector T cells by producing the anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-1 (6). Th17 and Treg cells represent two distinct phenotypes of CD4+ T cells with completely different functions. Th17 cells are proinflammatory, while Treg cells are anti-inflammatory. The balance established between these two subpopulations is crucial for preventing excessive immune activation, Posaconazole autoimmune responses, and metabolic syndrome pathogenesis. Th17 and Treg cell differentiation arising from naive precursors are mutually linked and can be controlled by the cytokine microenvironment and various metabolic states ( Figure?1 ). Open in Posaconazole a separate window Figure?1 Th17/Treg balance regulated by the cytokine microenvironment and cellular metabolic signaling pathways. Na?ve CD4+ T cells may differentiate into T helper cells (proinflammatory Th17 or anti-inflammatory Treg cells) according to specific cytokine profiles. Th17 cell differentiation can be induced by IL-6, IL-21, IL-23, IL-1, and TGF-. The proinflammatory cytokines IL-6, IL-21, and IL-23 activate STAT3 to induce gene expression and stimulate T cells towards Th17 cell differentiation. RORt promotes the expression of specific genes (e.g., the Th17 transcriptional program (10). Furthermore, TGF- is a developmental factor shared by Th17 and Treg cells. It induces the expression of both Foxp3 and RORt, and it drives the differentiation of iTreg cells into Th17 cells in a manner dependent on the presence of proinflammatory cytokines, such as IL-6, IL-1, and tumor necrosis factor (TNF)- (11). Thus, the balance established between Treg and Th17 cells is controlled by the action of proinflammatory or anti-inflammatory cytokines. IL-6 plays an important role in determining the direction of the differentiation pathway. Its absence drives the na?ve CD4 T cells towards differentiation into the Treg cells, while its presence promotes differentiation into Th17 cells (7). Metabolic Control of Th17 and Treg Cells Glycolysis, glutaminolysis, and fatty acid metabolism are the three main metabolic pathways in CD4+ T cells that function to provide energy. Activated T cells undergo remarkable metabolic changes that are characterized Posaconazole by metabolic reprogramming with increased glycolysis to support cell biosynthesis and function (12). Metabolic reprogramming is necessary during T-cell activation. Th17 cells, as effector T cells of the short-lived inflammatory T cell population, are hypothesized to rely more on glycolysis than the other metabolic pathways. Recent studies have revealed that aerobic glycolysis is indispensable for driving Th17 cell differentiation and function (13). Glycolysis is a series of cytosolic enzymatic reactions that catalyzes the conversion of glucose into pyruvate, thereby generating energy. Aerobic glycolysis is a metabolic process that involves the utilization of glucose to generate lactate with sufficient oxygen (14). It has been reported that glucose metabolism-related genes are highly expressed and expression levels of the intermediates, including pyruvate, lactate, and the pentose phosphate pathway, are enhanced in Th17 cells (15). Furthermore, the action of pyruvate kinase M2, the final rate-limiting enzyme in glycolysis, is necessary for Th17 differentiation (16). Inhibition of glycolysis, GHRP-6 Acetate such as that with 2-deoxy-d-glucose treatment, may inhibit Th17 cell development and cytokine production (17). Additionally, other metabolic pathways are involved in Th17 cell differentiation. The mechanism underlying glycolysis leading to Th17 cell polarization may be mediated by fatty acid synthesis (FAS). Indeed, Th17 cell function is dependent on fatty acid metabolism, thereby implicating the synthesis Posaconazole of several essential fatty acid derivatives in the regulation of Th17 cell function (18). The key enzyme of FAS is acetyl-CoA carboxylase (ACC), which catalyzes the carboxylation of acetyl-CoA into malonyl-CoA. Metabolic profiles of the fatty acid biosynthetic pathway have been shown to enhance Th17 cell differentiation and function (19). Th17 cell polarization is boosted by increased gene expression and RORt binding.