T CELL ENERGY: The metabolic pathways described above play a significant role in determining T cell functional outcomes. In the primary lymphoid organs, undifferentiated naïve T cells rely on mitochondrial OXPHOS for energy, as well as on extrinsic cell signals such as IL-7 to maintain energy for immune surveillance before activation [3]. Upon activation in the secondary lymphoid organs, a substantial change in the metabolism of naïve T cells allows them to differentiate into various Teff cells. Teffs such as activated CD4+ and CD8+ T cells depend on aerobic glycolysis for their bioenergetic demands due to the need for a rapid immune response [27]. In contrast to Teffs, Tregs use lipid metabolism instead of glycolysis [28] and mainly rely on OXPHOS generating long-lasting energy. Memory T cells (Tmem) also depend on FAO and OXPHOS for energy and have a high mitochondrial mass to generate energy rapidly in secondary exposure to the same antigen to execute rapid response. Notably, FAO is essential to maintain mitochondrial spare respiratory capacity (SRC) in Tmem cells. SRC is a functional parameter of mitochondria that measure maximum capacity of a cell to consume oxygen during stress [29]. Therefore, Treg and Tmem mainly rely on OXPHOS and FAO, for their energy demand, and express low levels of Glut1 and high rate of lipid oxidation that also further strengthen their dependency on FAO [28, 30]. As stated earlier, Teffs (Th1, Th2, and Th17) cells need glycolysis and to the lower extent rely on OXPHOS for their energy requirements and express high levels of Glut1 that underpins their high glycolytic nature [31]. Subsequent research studies demonstrated that Tregs have elevated expression of FAO related genes such as AMP-activated protein kinase (AMPK) compared to Th17 cells [32]. Previous research suggests that long chain FAO impart Tregs and Tmem cells survival. This conception is mainly due to inhibition of carnitine palmitoyltransferase 1A (CPT1A) with the drug etomoxir. CPT1A is the rate-limiting enzyme for long chain FAO and facilitate transport of long chain fatty acids into mitochondria for its β-oxidation. In turn, further findings show that Treg cells and Tmem cells utilize various pathways to transport fatty acids and use short- or medium-chain fatty acids whose translocation is not dependent on CPT1A [33,34]. Recent research shed new light that, engagement of the inhibitory pro­grammed cell death 1 (PD1) receptor on T cells with its ligand PD-L1 resulted in enhanced expression of CPT1A and elevated FAO. Hence, this engagement of PD1 prevents effector cell development [35]. Notably, PD1 is a crucial regulator of immune homeostasis, and its engagement increases the longevity of T cells in an oxidative environment. In marked contrast, cytotoxic T lymphocyte antigen 4 (CTLA4) inhibits glycolysis without augmenting CPT1A and FAO. Under normal conditions, Teffs cells downregulate FAO during their activation process and enhance fatty acid synthesis for their growth [27]. This downregulation of FAO by Teffs is attributed to Teffs functional inhibition and enhanced immune tolerance by FAO. Moreover, the glycolytic-lipogenic pathway and glutamine metabolism are used to fuel mitochondrial OXPHOS through the TCA cycle as an alternative input for the TCA cycle to support ATP production. It is mainly associated with Teffs differentiation through the mTOR pathway [36], which is the central player of CD4 T cells differentiation [37]. These different metabolic programs are tightly regulated to facilitate the energy production required for each distinct T cell subset. Glycolysis, OXPHOS, and glutaminolysis, are intertwined and properly managed to fulfill the bioenergetics demand of immune cells for proper proliferation and differentiation (Figure 1). Collectively, these studies indicate key roles of metabolic programming in determining T-cell fate and function along with other signals such as the strength of TCR stimulation, inflammatory cytokines and transcriptional factors [38, 39].