Metabolic Checkpoints During Tissue Inflammation

T cell encounters a variety of micro-environmental cues during differentiation into effector and regulatory T cells. The molecules which are essential for host metabolism affect and modulate T cells functions. In addition to antigen and cytokines, metabolic precursors, play a key role in activation, proliferation, and differentiation of T cells that lead to diverse immunological responses in tissue inflammation. An activated effector T cell undergoes a dramatic metabolic shift to support its growth, proliferation, differentiation, and functions. This metabolic shift occurs during T cells activation in tissue inflammation due to limited availability of oxygen and nutrients. Tumor infiltrating lymphocytes (TILs) are good example of such changes, where tumor microenvironment support less oxygen and glucose, which leads to metabolic shift in TILs (124–126). Under hypoxic environment in tumor, T cells express HIF-1α, which further modulate the course of immune response in tumors and its associated inflammation (127).

The metabolic shift known as Warburg effect is an essential phenomenon of active and growing T cells in tissue inflammation to support its energy demand in terms of ATP production and synthesis of biosynthetic precursor and intermediate molecules (128). The Warburg effect is particularly evident during tissue inflammation when activated T cell shifts toward aerobic glycolysis providing glucose-6-phosphate for the pentose phosphate pathway (PPP) generating 3-phosphoglycerate. This 3-phosphoglycerate is then utilized for the serine biosynthetic pathway which is essential for the biosynthesis of various cytokines required to induce effector functions of T cells in tissue inflammation. The aerobic glycolysis provides pyruvate to the TCA cycle leading to the synthesis of citrate, which is required for the membrane fatty acid synthesis (129). Metabolic reprogramming of T cells in tissue inflammation toward aerobic glycolysis further allow these cells to overcome stressful microenvironment, such as reduced cellular oxygen level, during tissue inflammation (130, 131). Moreover, lesser amount of ATP is generated through oxidative phosphorylation due to low levels of oxygen in the vicinity of tissues during inflammation (132, 133). Thus, aerobic glycolysis constitutes the major metabolic pathway in activated T cells, activated B cells, activated macrophages, DCs, stimulated natural killer cells and neutrophils during tissue inflammation (2, 9, 84, 134–139).

The metabolic reprogramming of T cells is well controlled at various metabolic checkpoints during homeostasis and inflammation. Metabolic shift toward aerobic glycolysis is supported by an enhanced expression of GLUT1 for increased glucose transport inside the cell for enhancing the rate of aerobic glycolysis (12). Interestingly, effector T cells efficiently adapts to hypoglycemia at the site of inflammation, where glucose levels are low. They do so by internalizing glutamine from their surrounding environment and catabolizes it through glutaminolysis for the continuity of TCA cycle (136). The glutamine supply to the differentiating effector T cells is crucial for maintaining Th1 cell differentiation, as it is observed that in the absence of glutamine during tissue inflammation, T cell skew toward Treg phenotype (140–142). Recently, similar role of amino acids such as leucine and arginine has also been established for differentiation and functions of effector T cells (143, 144).

The key players that bring about these metabolic reprogramming are mTOR and transcription factors such as Myc and HIF-1α as discussed above. Activity of these regulators in turn modulates the AMPK activity (145). mTOR activation is responsible for a number of dynamic changes within the proliferating activated T cells such as enhanced mRNA translation and fatty acid synthesis, maintenance of compartment Myc levels which in turn, is crucial for the induction of glycolytic gene expression (73, 143, 146, 147). Remarkably, different mTOR complexes triggers distinct metabolic programming that lead to effector vs. memory T cell generation (134). For example, mTORC1 signaling shifts the metabolism toward aerobic glycolysis during the proliferation of effector T cells; whereas mTORC2 is required for the metabolic reprogramming in memory T cells (134). Reduction of glycolysis together with an increased oxidative catabolism downregulate mTOR signaling, which skew T cells to become Tregs. Taken together it clearly indicates that mTOR serves as a key metabolic checkpoint for the development of effector and regulatory T cells that influences the outcome of tissue inflammation (111). The role of AMPK was also suggested in modulating effector and regulatory T cell response, as AMPK were shown to promote the development of regulatory and anti-inflammatory T cells while limiting the generation of effector T cells (145). Low cellular energy and insufficient nutrient supply trigger AMPK activation leading to inhibition of mTOR and upregulation of fatty acid catabolism, which support Tregs development and functions. In addition, at transcriptional level, upregulation of HIF-1α and Myc gene expression along with suppression of Bcl-6 is essential for the metabolic reprogramming in T cells during tissue inflammation (73, 84, 148, 149), which is initiated by Myc in CD4⁺ T cells while it is maintained further in CD8⁺ T cells by AP-4 and IRF4 transcription factors as soon as Myc activity declines (86, 150). Thus, these metabolic checkpoints play a crucial role in tissue inflammation and have enormous potential for immunotherapy.

Metabolic Checkpoints in Differentiation of Helper T Cells in Tissue Inflammation