*3.4. Importance of T Cell Metabolic Factors and the Level of Foxp3 Expression*

Differentiation, proliferation, and suppressive function or survival of Treg cells are influenced by various factors of energy metabolism. Therefore, the role of the Foxp3 protein in the regulation of cellular metabolism is also an important issue [127]. Naive T cells have modest metabolic requirements which are mainly related to the oxidation of pyruvate and fatty acids in the tricarboxylic acid (TCA) cycle [127]. However, when activated, the energy requirements of these cells increase. This is possible due to significant metabolic changes induced by the TCR receptor and costimulatory molecules such as phosphoinositol 3-kinase (PI3K) as well as AKT and rapamycin 1 (mTOR1) complexes, the activation of which are responsible for the regulation of genes responsible for the uptake and breakdown of glucose and other energetic compounds, including acids [127,128]. Such changes provide not only the energy needed for proliferation but also the necessary biosynthetic raw materials. According to conducted studies, inhibition of glycolysis may direct the differentiation of T CD4+ lymphocytes towards an anergic state which is then accompanied by an increased expression of the Foxp3 protein [128,129]. As a result of genetic or chemical ablation of mTOR and elimination of glycolysis facilitators, it causes the generation of iTreg cells compared to effector lines [130]. Additionally, the forced activation of AMP-activated protein kinase (AMPK), a regulator of lipid metabolism involved in T cell differentiation, leads to increased Foxp3 protein expression and iTreg cell differentiation [131,132]. Moreover, the use of fatty acid inhibitors such as etomixir or the carnitine palmitoyltransferase 1A inhibitor reduces the degree of differentiation of iTreg cells [133–135]. From studies conducted in recent years it can be concluded that the process of induction of Foxp3 protein expression by iTreg cells is extremely sensitive to metabolic factors [136]. In addition, mutations leading to inappropriate dominance of the T-lymphocyte glycolytic pathway destabilize the Treg cell phenotype and result in the loss of the ability to express the Foxp3 protein which then leads to the inability of cells to suppress inflammation [127–129].
