CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or ...oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.
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•CD4 T cells express multiple glucose transporters, including Gluts 1, 3, 6, and 8•Glut1 has nonredundant function in activated, but not resting, CD4 T cells•CD4 Th1 and Th17 selectively require Glut1 in vivo to regulate immunologic diseases•Targeting T cell glucose metabolism in vivo can selectively impact effector cells
T cells undergo distinct metabolic reprogramming events upon activation and differentiation to inflammatory effectors or regulatory cells. Macintyre et al. show that Glut1 is the only glucose transporter required to drive glycolysis for growth and expansion of effector, but not resting or regulatory, CD4 T cells and induce inflammatory diseases.
Leptin is an adipokine secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper ...17 (Th17) cell number and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context.
Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined.
In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Specifically, we observed increased T cell oxidative metabolism, increased CD4+ T cell IFN-γ expression, and increased proportion of T regulatory (Treg) cells in control mice fed high-fat diet compared to low-fat diet, which were not observed in the leptin receptor conditional knockout mice, suggesting that leptin receptor signaling is required for some of the inflammatory changes observed in T cells in obesity.
T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity.
B cell activation leads to proliferation and Ab production that can protect from pathogens or promote autoimmunity. Regulation of cell metabolism is essential to support the demands of lymphocyte ...growth and effector function and may regulate tolerance. In this study, we tested the regulation and role of glucose uptake and metabolism in the proliferation and Ab production of control, anergic, and autoimmune-prone B cells. Control B cells had a balanced increase in lactate production and oxygen consumption following activation, with proportionally increased glucose transporter Glut1 expression and mitochondrial mass upon either LPS or BCR stimulation. This contrasted with metabolic reprogramming of T cells, which had lower glycolytic flux when resting but disproportionately increased this pathway upon activation. Importantly, tolerance greatly affected B cell metabolic reprogramming. Anergic B cells remained metabolically quiescent, with only a modest increase in glycolysis and oxygen consumption with LPS stimulation. B cells chronically stimulated with elevated BAFF, however, rapidly increased glycolysis and Ab production upon stimulation. Induction of glycolysis was critical for Ab production, as glycolytic inhibition with the pyruvate dehydrogenase kinase inhibitor dichloroacetate sharply suppressed B cell proliferation and Ab secretion in vitro and in vivo. Furthermore, B cell-specific deletion of Glut1 led to reduced B cell numbers and impaired Ab production in vivo. Together, these data show that activated B cells require Glut1-dependent metabolic reprogramming to support proliferation and Ab production that is distinct from T cells and that this glycolytic reprogramming is regulated in tolerance.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to ...support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5′ AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.
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•Primary T-ALL cells adopt aerobic glycolysis for cell survival and disease progression•T-ALL glucose metabolism is far lower than the capacity of activated T cells•Primary T-ALL cells are ATP depleted and exhibit chronic metabolic stress•AMPK both inhibits anabolic metabolism and is essential for T-ALL cell survival
Kishton et al. reveal that glycolysis is selectively restrained in T-ALL cells compared to activated T cells. Oncogenic Notch signaling in T-ALL activates AMPK, which inhibits anabolic metabolism while also promoting T-ALL cell survival through oxidative metabolism. AMPK deficiency or Complex I inhibition triggers T-ALL cell death and reduces disease burden.
CD4
effector T cells (T
cells) and regulatory T cells (T
cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K ...(phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for T
cell proliferation and inflammatory function, the mechanisms that regulate T
cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote T
cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired T
cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of T
cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of T
cells.
Insulin and insulin-like growth factor 1 (IGF-1) are metabolic hormones with known effects on CD4
T cells through insulin receptor (IR) and IGF-1 receptor (IGF-1R) signaling. Here, we describe ...specific and distinct roles for these hormones and receptors. We have found that IGF-1R, but not IR, expression is increased following CD4
T cell activation or following differentiation toward Th17 cells. Although both insulin and IGF-1 increase the metabolism of CD4
T cells, insulin has a more potent effect. However, IGF-1 has a unique role and acts specifically on Th17 cells to increase IL-17 production and Th17 cell metabolism. Furthermore, IGF-1 decreases mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS) in Th17 cells, providing a cytoprotective effect. Interestingly, both IR and IGF-1R are required for this effect of IGF-1 on mitochondria, which suggests that the hybrid IR/IGF-1R may be required for mediating the effect of IGF-1 on mitochondrial membrane potential and mROS production.
Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require ...distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.
Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically ...distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.
Upon activation, T cells require energy for growth, proliferation, and function. Effector T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism to fuel ...proliferation and function. In contrast, Treg cells require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg‐cell metabolism is altered when nutrients are limited and leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells. We found that both malnutrition‐associated hypoleptinemia and T cell‐specific leptin receptor knockout suppressed Teff‐cell number, function, and glucose metabolism, but did not alter Treg‐cell metabolism or suppressive function. Using the autoimmune mouse model EAE, we confirmed that fasting‐induced hypoleptinemia altered Teff‐cell, but not Treg‐cell, glucose metabolism, and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF‐1α, a key regulator of Th17 differentiation and Teff‐cell glucose metabolism, and found HIF‐1α expression was decreased in T cell‐specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data demonstrate a selective, cell‐intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg cells.
We have found that the adipocyte‐secreted hormone leptin is responsible for promoting Teff‐cell glycolytic metabolism and cytokine production, in part through activation of the signaling protein HIF‐1α. In malnutrition, or following fasting, low leptin levels prevent Teff‐cell metabolism and activation and thereby protect against select forms of autoimmunity, including EAE.
Obesity is an independent risk factor for increased influenza mortality and is associated with impaired memory T-cell response, resulting in increased risk of infection. In this study, we ...investigated if weight loss would restore memory T-cell response to influenza.
Male C57BL/6J mice were fed either low-fat or high-fat diet to induce obesity. Once obesity was established, all mice received primary infection with influenza X-31. Following a recovery period, we switched half of the obese group to a low-fat diet to induce weight loss. Fifteen weeks after diet switch, all mice were given a secondary infection with influenza PR8, and memory T-cell function and T-cell metabolism were measured.
Following secondary influenza infection, memory T-cell subsets in the lungs of obese mice were decreased compared to lean mice. At the same time, T cells from obese mice were found to have altered cellular metabolism, largely characterized by an increase in oxygen consumption. Neither impaired memory T-cell response nor altered T-cell metabolism was reversed with weight loss.
Obesity-associated changes in T-cell metabolism are associated with impaired T-cell response to influenza, and are not reversed with weight loss.
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