Activated T cells use glucose metabolism to fulfill the metabolic requirements for rapid proliferation and biosynthesis supporting cellular growth and differentiation (4). Such demands are met, in part, by upregulation of glucose transporter 1 (Glut1) during T cell activation. Naïve T cells express low levels of Glut1 on the cell surface, but Glut1 expression and surface localization are significantly increased in activated T cells (8–10). Several upstream signals regulate Glut1 expression in T cells. TCR and CD28 co-stimulation induces the expression and surface localization of Glut1 in T cells (10). The phosphoinositol-3 kinase (PI(3)K)-Akt pathway triggers the translocation of Glut1 from cytoplasm to T cell surface (9, 10). Other stimuli also increase surface Glut1 levels on T cells; for example, IL-7-induced STAT5 signaling and downstream Akt activation induce Glut1 trafficking to the cell surface in both naïve and activated T cells (11). Increased surface expression of Glut1 is observed on memory CD4⁺ T cells upon insulin stimulation through a mechanism that requires Notch-Akt signaling (12). In human CD4⁺ T cells, the SLC2a1 (encodes for human Glut1) mRNA transcript is targeted by miR-150, whose expression is downregulated by co-stimulation with the complement receptor CD46 (13). CD46 signaling is also important for effective T_H1 cell differentiation by potentiating TCR-driven Glut1 expression and surface translocation (14).

Extensive efforts have been made to determine the role of Glut1 in T cell responses. While Glut1 overexpression does not alter T cell development, it enhances activated T cell proliferation and growth (10, 15), and generation of T_FH cells (16). Also, T_H1, T_H2, and T_H17 cells express high levels of Glut1 and are highly glycolytic (15, 17). Consistent with this observation, conditional deletion of Slc2a1 (encodes for mouse Glut1) in the T cell compartment leads to defective generation of T_H1, T_H2, and T_H17 cells both in vitro and in vivo (8). How Glut1 expression and glucose metabolism specifically contribute to the functional specialization of effector CD4⁺ T cell subsets requires further investigation. Transgenic expression of Glut1 leads to an accumulation of activated/memory phenotype T cells in vivo, suggesting a role of glucose metabolism in T cell memory responses (10, 15). Memory T cells have reduced glycolysis as compared to effector T cells (18), but Glut1 expression and glucose uptake are essential for CD4⁺ memory T cell maintenance (12). A recent study demonstrates that constitutive glycolysis promotes the formation of effector memory CD8⁺ T cells (T_EM) in a murine genetic model with T cell-specific deletion of a key hypoxia-inducible factor 1α (HIF1α) negative regulator, Von Hippel-Lindau (VHL) (19). Consistent with these observations, Glut1 expression favors human T_EM formation (20). Moreover, the rapid acquisition of effector functions by human T_EM requires immediate-early glycolysis upon activation (21). Thus, Glut1 and glucose metabolism are essential for effector and T_EM responses. Further studies are required to reveal the underlying molecular mechanisms.

Recent studies have uncovered important roles of glucose competition between tumor cells and effector T cells within the tumor microenvironment (22–24). Similar to T cells, tumor cells rewire their metabolism to greatly increase glucose uptake and aerobic glycolysis, which is known as the Warburg Effect (25). The functional state of tumor-infiltrating T cells is positively correlated with their glycolytic activity and glucose availability within tumor tissues (23, 24). Due to the limited glucose levels in the tumor microenvironment, tumor-infiltrating T cells produce less IFN-γ than T cells taken from glucose-replete environments (23). Mechanistically, this is linked to the ability of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to serve as both a glycolytic enzyme and RNA-binding protein (26, 27). When aerobic glycolysis is inhibited, GAPDH binds to the Ifng (encodes for IFN-γ) mRNA transcript to suppress its translation (28). Aerobic glycolysis also plays a pivotal role in sustaining TCR-mediated calcium-NFAT signaling to maintain T cell effector functions (24). Specifically, phosphoenolpyruvate (PEP) generated during glycolysis maintains cytosolic calcium levels by suppressing sacro/endoplasmic reticulum calcium ATPase activity (24). Notably, increasing PEP production enhances anti-tumor T cell responses (24). Removing the metabolic restrictions in T cells may also contribute to the therapeutic effects of checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibody administrations, since those treatments restore glucose levels within tumors and glycolytic metabolism in T cells (23). More research is needed to determine the therapeutic potential of targeting the components of glucose sensing and metabolism in T cells in cancer patients.

The roles of glycolytic metabolism have also been investigated in suppressive Foxp3⁺ T_reg cells. Murine T_reg cells express comparable levels of Glut1 as naïve T cells but lower levels of Glut1 than effector T cells (8, 15). Such regulation of Glut1 expression is partially dependent on elevated AMP-activated protein kinase (AMPK) activation in T_reg cells (15). Foxp3, the master transcription factor that governs T_reg cell differentiation and function, limits Glut1 expression through inhibiting Akt (29). Glut1 deficiency does not affect T_reg cell suppressive function but increases the proportion of T_reg cells in the peripheral CD4⁺ T cell compartment (8). In contrast, T_reg cells with aberrant increases in glucose metabolism tend to lose their lineage stability. Indeed, murine T_reg cells with elevated Glut1 expression have reduced CD25 and Helios expression and are unable to maintain Foxp3 expression and suppressive function in a murine inflammatory bowel disease model, indicative of reduced T_reg cell stability (30). These results are consistent with recent findings that aberrant glycolysis is detrimental to T_reg cell lineage stability and functional integrity (31–33). Of note, proliferating human and murine T_reg cells have elevated glucose uptake and glycolysis than non-dividing T_reg cells, and glycolysis contributes to the functional differentiation of human T_reg cells by inducing FOXP3 expression (34, 35). These studies highlight a pivotal role of glucose metabolism in balancing the proliferation and suppressive function of T_reg cells, which is likely important for controlling effector and suppressive T cell responses during infection and inflammation.

Amino acids are critical for efficient T cell activation and proliferative responses (36). The SLC7 amino acid transporter family contributes to the uptake of amino acids by T cells. The SLC7 amino acid transporter family is comprised of the cationic amino acid transporters (SLC7A1-4, CAT1-4, and SLC7A14) and the glycoprotein-associated amino acid transporters (SLC7A5-13, SLC7A15) (37). Antigen signaling through the TCR increases phenylalanine, leucine, and glutamine uptake into CD8⁺ T cells (38, 39). Furthermore, the expression of many SLC7 transporters, including Slc7a5 (encodes for LAT1), is upregulated during activation in both mouse and human T cells (38, 40), which may be mediated by TCR-induced ERK/MAPK signaling (39). LAT1 associates with CD98 (encoded by Slc3a2) to form a high-affinity transporter that facilitates the bidirectional influx of leucine and efflux of glutamine from cells (38, 41). LAT1 is not required for normal T cell development; however, LAT1-deficient CD8⁺ T cells have impaired primary effector expansion following antigenic stimulation (38). Mechanistically, leucine uptake induces activation of mechanistic target of rapamycin complex 1 (mTORC1) in effector CD8⁺ T cells and promotes c-Myc expression (38). Furthermore, the loss in c-Myc expression in CD8⁺ T cells correlates with impaired glucose, glutamine, and arginine uptake and impaired glycolytic metabolism, which promote proper CD8⁺ T cell effector function (38, 42). Thus, leucine is a positive regulator of peripheral CD8⁺ T cell functionality. There is much left to be understood how amino acid sensing regulates CD8⁺ T cell responses. For instance, while glutamine receptor ASCT2 (encoded by Slc1a5) is dispensable for CD8⁺ T cell development (41), how ASCT2 regulates CD8⁺ T cell effector and memory responses has not been explored.

Both leucine and glutamine are positive regulators of CD4⁺ T cell differentiation into T_H1 and T_H17 cells. Indeed, the absence of LAT1 expression impairs T_H1 and T_H17 cell differentiation in vitro (38), and elevated glutamine levels favor T_H1 and T_H17 cell differentiation in vitro (41). Consistent with these observations, ASCT2 is important for T_H1 and T_H17 cell differentiation (41). Likely due to the bidirectional transport of glutamine and leucine via LAT1, activated ASCT2-deficient CD4⁺ T cells also have decreased leucine uptake (41, 43). Interestingly, highly elevated leucine levels favor T_H17 differentiation, but impair T_H1 differentiation in vitro, indicating that high concentrations of leucine may negatively regulate T_H1 differentiation (41). Glutaminolysis plays crucial roles in replenishing the TCA cycle under conditions of aerobic glycolysis and supports T cell activation (42). Furthermore, the glutamine-derived metabolite alpha-ketoglutarate promotes T_H1 differentiation, potentially through enhancing mTORC1 signaling (44). Unlike T_H1 and T_H17 cells, T_H2 and T_reg cells do not require the expression of LAT1 or ASCT2 for their differentiation in vitro (38, 41), likely due to their altered dependency on mTOR signaling (45). Indeed, T_reg cell differentiation is favored during glutamine deprivation (44). Thus, leucine and glutamine likely act in concert to regulate the threshold of mTORC1 signaling and subsequent CD4⁺ T cell differentiation.

Arginine is transported into cells through the cationic transporters CAT1-4 (46), where it is metabolized by arginase 1 or nitric-oxide synthase 2 (46). Myeloid-derived suppressor cells, which are elevated in tumor microenvironment and other disease states, consume and deplete extracellular arginine (46). These arginine-depleted environments impair T cell proliferation (47–50). Arginine is also directly metabolized in T cells (51). Activated T cells have increased l-arginine metabolism mediated by arginase 2, which contributes to enhanced CD4⁺ and CD8⁺ T cell survival and anti-tumor immunity (51). Interestingly, Arg2-deficient CD4⁺ and CD8⁺ T cells have elevated levels of intracellular l-arginine, which correlates with increased survival after IL-2 withdrawal (51), suggesting that additional arginine-sensing pathways contribute to T cell survival. While the mechanisms of how arginine is sensed within T cells remain elusive, BAZ1B, PSIP1, and Translin are potential arginine sensors that promote T cell survival (51). Interestingly, these survival effects appear to be independent of modulating mTORC1 activation, which is a known downstream sensor of arginine in other cell lineages (52–54). Thus, regulation of arginine availability and sensing is critical for T cell functionality and combating environmental insults, such as infections and tumors. Future studies can explore how lysine and ornithine, whose uptake is also CAT dependent, contribute to T cell responses.

Serine is a non-essential amino acid that is synthesized intracellularly from the glycolytic intermediate 3-phosphoglycerate, or directly transported into cells (55). Recent work reveals that serine metabolism is enhanced in activated T cells and provides intracellular glycine and one-carbon units for purine nucleotide biosynthesis, thereby supporting T cell proliferation (56). Serine uptake is critical for effector T cell responses, as serine and glycine-limiting conditions impair anti-CD3/CD28 antibody-driven CD4⁺ and CD8⁺ T cell proliferation in vitro (56). Furthermore, mice on a serine and glycine-restricted diet have impaired antigen-driven CD8⁺ effector T cell expansion and pathogen clearance (56). These findings elucidate a novel role for serine metabolism in effector T cell responses.

Indoleamine 2,3-dioxygenase (IDO) catabolizes the amino acid tryptophan, resulting in localized tryptophan depletion. Tryptophan depletion is then sensed by general control non-derepressible 2 (GCN2), which has a high affinity for uncharged tRNAs that accumulate when intracellular amino acid abundance is low. GCN2 binding to uncharged tRNAs induces GCN2 kinase activity, which subsequently inhibits protein translation via the phosphorylation of eIF2α (6). It has been demonstrated that GCN2 sensing of amino acid deprivation in activated T cells promotes T cell survival, limits T cell proliferation, and induces T cell anergy (36, 57). In contrast to these findings, a recent study has shown that both control and GCN2-deficient CD4⁺ and CD8⁺ T cells have impaired proliferation when tryptophan, arginine, lysine, leucine, or asparagine levels are low, suggesting additional pathways contribute to sensing amino acid deprivation in T cells (58). IDO may also influence T cell responses independently of GCN2 kinase activity by altering the inflammatory environment. Indeed, tryptophan metabolites promote T_reg cell differentiation indirectly by increasing TGF-β production by dendritic cells (DCs) (59). Furthermore, blocking IDO promotes IL-6 production by plasmacytoid DCs, which enables skewing of CD4⁺ T cells toward the T_H17 cell subset and suppression of T_reg cell development (60, 61). Consequently, IDO deficiency promotes T_H17 differentiation and exacerbates experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis (59). Thus, the IDO-tryptophan degradation pathway plays a regulatory role in local inflammation driving T_H17 cell responses.

The basic structure of a FA is a carboxylic acid linked to a saturated or unsaturated aliphatic chain. FAs are categorized broadly into groups based on the length of the aliphatic chain. Short-chain fatty acids (SCFAs) have 2–6 carbons; medium chain fatty acids have 7–12 carbons; and long chain fatty acids (LCFAs) have more than 12 carbons (62). Some FAs are generated within the cell through de novo synthesis; however, many important FAs cannot be synthesized and are obtained only through dietary sources. For instance, when dietary fats and fibers are catabolized in the liver and intestines, respectively, free fatty acids (FFAs) are generated and circulate through the blood (62). Although certain FFAs can diffuse across the plasma membrane into the cytosol, most require transport facilitated by surface receptors. LCFAs and oxidized FAs are transported across the membrane by fatty acid translocase (FAT or CD36) (63). Additionally, several G protein receptors bind FAs of various lengths—GPCR40 (free fatty acid receptor 1) and GPCR120 bind to LCFAs; GPCR84 recognizes MCFAs; GPCR43 (FFA2) and GPCR41 (FFA3) bind to SFCAs (62).

Several studies have revealed roles for SFCAs and their transporters in T cell responses. The breakdown of dietary fibers into acetate, butyrate, and propionate by intestinal bacteria plays an important role in controlling T cell inflammatory responses. For instance, within the intestines, these SCFAs bind the GPCR43 receptor on T_reg cells and promote their differentiation and function to maintain intestinal homeostasis (64, 65). Mechanistically, butyrate inhibits histone deacetylase (HDAC) activity, subsequently enhancing histone acetylation in the Foxp3 promoter to promote stable Foxp3 expression (64, 66, 67). Interestingly, these intestine-derived SCFAs also promote the generation of T_reg cells in distal tissues (66) and shape inflammatory responses within the central nervous system, kidneys, and lungs (68–71). For example, during an acute Listeria monocytogenes infection, serum levels of acetate increase, which is required for optimal memory CD8⁺ T cell formation (72). The increase in intracellular acetate enhances glycolytic activity necessary for a rapid recall response by CD8⁺ T cells (72). Mechanistically, the accumulation of acetate drives GAPDH acetylation to increase glycolytic flux (72). Furthermore, SCFA-mediated inhibition of HDAC activity increases the acetylation of S6K. This process promotes T_H1 and T_H17 cell differentiation and induces IL-10 production by CD4⁺ T cells (70). These studies show the pleiotropic functions of SCFAs in immune responses and provide evidence for targeting FA sensing pathways to modulate T cell responses.

Intracellular FAs are also recognized by peroxisome proliferator-activated receptors (PPARs). The PPAR family of nuclear receptors has three isoforms: PPARα, PPARδ, and PPARγ. After recognizing their ligands, PPARs associate with the retinoid X receptor heterodimer, which binds PPAR-responsive elements to promote gene transcription (73). PPARγ is an important regulator of effector T cell functions, as PPARγ-deficient CD4⁺ T cells cannot proliferate and survive in a lymphopenic environment and hence are less capable of inducing autoimmunity and graft-versus-host disease in mice (74). Antagonizing PPARγ promotes T_H17 cell differentiation and increases the severity of EAE (75, 76). Excessive T_H17 cell differentiation might also be linked to the role of PPARγ in T_reg cell differentiation. Indeed, PPARγ is essential for the maintenance and accumulation of T_reg cells in adipose tissue (77). Thus, PPARγ serves as a key regulator of CD4⁺ T cell function and differentiation.

To facilitate ligand recognition and initiate efficient signaling, several TCRs must oligomerize into nanoclusters (78). This process is controlled by cholesterol and its derivatives. Cholesterol-facilitated nanoclustering of TCRs enhances the avidity of the TCR toward its ligand (79). Conversely, cholesterol sulfate and cholesterol esters antagonize TCR function by displacing cholesterol and disrupting the formation of nanoclusters (80). Interestingly, cholesterol may serve temporal or spatial roles in TCR signaling. Cholesterol is an allosteric inhibitor of the TCRβ transmembrane domain and hence limits spontaneous TCR activation; however, the spontaneous unbinding of cholesterol in this region switches the conformation from inactive to active, allowing for the transmission of TCR signals (81). Therefore, cholesterol level in the plasma membrane of T cells is important for regulating TCR activity, which may contribute to T cell development and functions under different conditions.

Intracellular concentrations of cholesterol play key roles in both development and effector functions of T cells. Inhibition of the esterification enzyme acetyl-coenzyme A acetyltransferases 1 increases cholesterol content in the plasma membrane of CD8⁺ T cells, which augments TCR nanoclustering and subsequently increases effector CD8⁺ T cell functions (82). Furthermore, deletion of ATP-binding cassette sub-family G member 1 (ABCG1), a protein promoting cholesterol efflux from cell, leads to an accumulation of intracellular cholesterol in T_reg cells and increase in T_reg cell frequency. Mechanistically, loss of ABCG1 and subsequent disruption in intracellular cholesterol distribution decreases mTOR activity and increases STAT5 signaling, thereby promoting T_reg cell formation (83). These data demonstrate that intracellular cholesterol levels are essential for T cell function.

Cholesterol and its derivatives can also serve as intracellular ligands to influence T cell differentiation and function. Specifically, cholesterol derivatives control T_H17 cell differentiation by modulating liver X receptor (LXR) and retinoic acid responsive-related orphan receptor γt (RORγt) activity. LXR engagement antagonizes T_H17 cell development by mediating the binding of sterol response element-binding protein (SREBP)1 to the Il17a locus and blocking the upregulation of aryl hydrocarbon receptor (AHR) necessary to induce Il17a transcription (84). Additionally, many cholesterol biosynthetic intermediates and derivatives are natural ligands for RORγt, the master transcription factor for T_H17 cell development (85–87). These derivatives include oxysterol, desmosterol, and many cholesterol intermediates generated between lanosterol and zymosterol biosynthesis. Pharmaceutical or genetic disruption of these metabolites limits T_H17 cell generation and ameliorates the severity of EAE (85–87). If and how cholesterol intermediates influence other effector CD4⁺ T cell differentiation require further investigation.

The ability to sense cholesterol and generate de novo cholesterol is also critical for the activation and effector functions of T cells. Cholesterol synthesis is regulated within the cell by the transcription factor, SREBP2, and its chaperone SREBP cleavage activating protein (SCAP), which helps sense intracellular cholesterol levels (88). T cell activation induces the activation of SULT2B1, an oxysterol-metabolizing enzyme, which indirectly enhances SREBP2-dependent cholesterol synthesis by limiting oxysterols that activate LXR. Thus, SULT2B1 limits cholesterol export from the cell by blocking the LXR-dependent upregulation of cholesterol-modifying enzymes and transporters (89). Intrinsic SCAP expression is required for T cell proliferation and effector function (90). While SCAP-deficient T cells develop normally and are capable of undergoing homeostatic proliferation, they do not generate the requisite lipids for cell growth induced by TCR stimulation (90). Whether SCAP deficiency affects TCR nanonclustering is unknown, but early TCR signaling is not impaired in the absence of SCAP despite these cells having reduced total cholesterol.

TCR stimulation-induced lipid biosynthesis is dependent on mTORC1 activation (90). Naïve CD4⁺ T cells deficient in Raptor, an obligatory component of mTORC1, neither efficiently upregulate the expression of SREBP or other cholesterol-related genes nor appropriately grow and proliferate upon TCR and CD28 co-stimulation. These defects in cholesterol synthesis, along with compromised glycolysis and oxidative phosphorylation, are correlated with a reduced capacity to differentiate into effector CD4⁺ T cells (91). Raptor-deficient T_reg cells also have reduced cholesterol-related gene expression, which severely compromises T_reg cell proliferation and suppressive function (92).

Of interest, the energy production and suppressive capacity of T_reg cells are also linked to FA oxidation (FAO) (15), similar as memory CD8⁺ T cells (18). Memory CD8⁺ T cells fuel FAO via de novo lipid synthesis to support their homeostasis (18, 93). Additionally, de novo FA synthesis is crucial for the regulation of T_reg and T_H17 cell differentiation. Inhibition of acetyl-CoA carboxylase-1 (ACC1), a key enzyme for FA synthesis, promotes T_reg cell and inhibits T_H17 cell differentiation. Mechanistically, ACC1 deficiency limits FA synthesis and glycolysis needed for T_H17 cell development (94). While the low level of exogenous FA intake may be enough to sustain T_reg cells (94), future studies can explore if such interplay between FAO and de novo lipid synthesis and/or cholesterol catabolism contributes to T_reg cell functions. Furthermore, identifying and characterizing the physiological function of additional sterol-related metabolites in T cell responses may provide a novel approach to treat inflammatory diseases.

Energy homeostasis is the basis of cell survival and function. AMPK is directly activated by an increased cellular AMP to ATP concentration during energy deprivation. AMPK functions as a fundamental regulator of T cell metabolism to inhibit anabolic pathways and to promote catabolic pathways to preserve cellular energy homeostasis (110). While the activation, regulation, and signaling of AMPK has been reviewed elsewhere (7, 111), here we will briefly discuss the functions of AMPK in T cells (Figure 5). AMPK is activated in glucose-deprived CD8⁺ T cells experiencing energy stress, such as during infection and inflammation. AMPK is critical for both primary and memory CD8⁺ T cell responses to infections (112, 113). In nutrient-limiting tumor microenvironment, CD8⁺ T cells also require AMPK activation for their survival to defend against tumors (114). The pro-survival functions of AMPK could also be linked to the induction of macroautophagy, which is discussed in detail below (115).

In activated T cells, AMPK is a master regulator of cellular metabolism. It preserves energy homeostasis by suppressing mRNA translation and promoting glutamine-fueled mitochondrial oxidization in response to glucose deprivation (112). The differentiation of T_H1 and T_H17 cells from naïve CD4⁺ T cells does not require AMPK activity, but their accumulation and their ability to induce inflammation in the colon are severely impaired in the absence of AMPK (112). However, AMPK activation is detrimental to T cell responses in certain contexts. In response to nutrient stress and DNA damage, active AMPK induces p38-dependent senescence in human CD4⁺ T cells, and silencing of AMPK restores telomerase activity and proliferation in senescent T cells (116). Aberrant AMPK activation is linked to impaired T_FH cell generation in T cells deficient in the ROQUIN RING domain (117). The AMPK agonist, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), inhibits T_H17 cell induction and promotes T_reg cell generation in vitro (118), but these results should be interpreted cautiously due to the reported off-target effects of AICAR (119). Therefore, by sensing energy stress, AMPK plays a pivotal role in metabolic reprogramming to regulate T cell responses.

Macroautophagy, hereafter referred to as autophagy, is an evolutionarily conserved cellular process that breaks down endogenous cytosolic materials and organelles (127). Autophagy helps regulate energy consumption and cellular resources during cellular stress. Indeed, amino acid starvation and other energy-stressing conditions induce autophagy, which in part depends upon AMPK and mTORC1 signaling (128). How nutrient availability regulates autophagy in T cells remains elusive. Earlier in vitro studies showed evidence for increased autophagy in T cells after TCR and cytokine stimulation (129–131). However, in vivo, virus-specific CD8⁺ T cells downregulate autophagy during clonal expansion (132). In contrast, during the contraction phase, autophagy is upregulated in virus-specific CD8⁺ T cells (132). Furthermore, upregulation of autophagy is critical for CD8⁺ T cell memory formation, as acute deletion of Atg7 or Atg5 in peripheral CD8⁺ T cells impairs survival during the contraction phase, resulting in a decreased memory CD8⁺ T cell pool (132). Thus, the regulation of autophagy during the kinetics of T cell responses is dynamic. The contribution of cellular stress conditions, such as nutrient levels, growth factor withdrawal, energy, and oxidative stress, in regulating autophagy and effector T cell responses remains to be further elucidated.

Recent studies have shown that autophagy regulates CD4⁺ T cell lineage differentiation and functionality. T_reg cells have increased autophagosomes compared to conventional CD4⁺ T cells (33, 133, 134). T_reg cell-specific deletion of genes required for autophagy (Atg7, Atg5, Atg16l1) reduces T_reg cell survival, stability of Foxp3 expression and ability to control pro-inflammatory CD4⁺ T cell responses (33, 133). Furthermore, loss of autophagy in T_reg cells aberrantly elevates mTORC1 and c-Myc expression, which enhances glycolysis and limits T_reg cell stability and function (33). This is in contrast to autophagy-dependent reactivation of mTORC1 signaling under conditions of sustained nutrient deprivation (135). Interestingly, the microenvironment may alter the role of autophagy in T cells, as Atg16l1-deficient CD4⁺ T cells had elevated T_H2 cell responses selectively within the intestinal environment (133). How autophagy regulates mTORC1 signaling is not completely understood. In T_reg cells, autophagy may selectively target PI(3)K-related signaling proteins for degradation (33). In effector T cells, autophagy selectively degrades Bcl-10, affecting the signaling between TCR and NF-κB (136). Interestingly, the CARMA1/Bcl-10/MALT1 complex contributes to the upregulation of ASCT2 expression and glutamine uptake in TCR activated T cells, which controls mTORC1 activation (41). Thus, the role of autophagy in T cells is complex, as it not only regulates cellular degradation in times of nutrient deprivation but also serves to modulate TCR signaling.