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Aim: To investigate if patients with diabetes taking metformin have better outcomes versus those not taking metformin following an emergency room visit for influenza. Methods: Using electronic medical records, we performed a retrospective chart review of all adult patients with a diagnosis of diabetes seen in any Duke University Medical Center‐affiliated emergency department for influenza over a 6‐year period. We documented patient characteristics and comorbidities, and compared outcomes for patients taking metformin versus patients not taking metformin using both univariable and multivariable analyses. Our primary outcome was hospital admission rate. Secondary outcomes were in‐hospital length of stay and in‐hospital death. Results: Our cohort included 1023 adult patients with diabetes, of whom 59.9% were female. The mean age was 62.9 years, 58.4% were African American, 36.1% were White, and 81.9% were obese or overweight. Of these patients, 347 (34%) were taking metformin. Patients with diabetes taking metformin were less likely to be hospitalized following an emergency department visit for influenza than patients with diabetes not taking metformin (56.8% vs. 70.1%; p < 0.001). Of those patients admitted, there was no statistically significant difference in length of stay or death. Conclusions: In patients with diabetes, metformin use is associated with lower rate of hospitalization following an emergency department visit for influenza. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Activation of [CD4.sup.+] T cells results in rapid proliferation and differentiation into effector and regulatory subsets. [CD4.sup.+] 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.sup.+] 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.sup.+] 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.sup.+] subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases., Introduction [CD4.sup.+] T lymphocytes are critical to mediating or suppressing normal immunity as well as inflammatory or autoimmune diseases. Antigen exposure initially leads to T cell activation, inducing rapid growth [...]

Background Obesity dysregulates immunity to influenza infection. Therefore, there is a critical need to investigate how obesity impairs immunity and to establish therapeutic approaches that mitigate the impact of increased adiposity. One mechanism by which obesity may alter immune responses is through changes in cellular metabolism. Methods We studied inflammation and cellular metabolism of peripheral blood mononuclear cells (PBMCs) isolated from individuals with obesity relative to lean controls. We also investigated if impairments to PBMC metabolism were reversible upon short-term weight loss following bariatric surgery. Results Obesity was associated with systemic inflammation and poor inflammation resolution. Unstimulated PBMCs from participants with obesity had lower oxidative metabolism and adenosine triphosphate (ATP) production compared to PBMCs from lean controls. PBMC secretome analyses showed that ex vivo stimulation with A/Cal/7/2009 H1N1 influenza led to a notable increase in IL-6 with obesity. Short-term weight loss via bariatric surgery improved biomarkers of systemic metabolism but did not improve markers of inflammation resolution, PBMC metabolism, or the PBMC secretome. Conclusions These results show that obesity drives a signature of impaired PBMC metabolism, which may be due to persistent inflammation. PBMC metabolism was not reversed after short-term weight loss despite improvements in measures of systemic metabolism. [ABSTRACT FROM AUTHOR]

Background: Malnutrition, including obesity and undernutrition, among children is increasing in prevalence and is common among children on renal replacement therapy. The effect of malnutrition on the pre‐transplant immune system and how the pediatric immune system responds to the insult of both immunosuppression and allotransplantation is unknown. We examined the relationship of nutritional status with post‐transplant outcomes and characterized the peripheral immune cell phenotypes of children from the Immune Development of Pediatric Transplant (IMPACT) study. Methods: Ninety‐eight patients from the IMPACT study were classified as having obesity, undernutrition, or normal nutrition‐based pre‐transplant measurements. Incidence of infectious and alloimmune outcomes at 1‐year post‐transplantation was compared between nutritional groups using Gray's test and Fine‐Gray subdistribution hazards model. Event‐free survival was estimated by Kaplan–Meier method and compared between groups. Differences in immune cell subsets between nutritional groups over time were determined using generalized estimating equations accounting for the correlation between repeated measurements. Results: We did not observe that nutritional status was associated with infectious or alloimmune events or event‐free survival post‐transplant. We demonstrated that children with obesity had distinct T‐and B‐cell signatures relative to those with undernutrition and normal nutrition, even when controlling for immunosuppression. Children with obesity had a lower frequency of CD8 Tnaive cells 9‐month post‐transplant (p <.001), a higher frequency of CD4 CD57 + PD1‐ T cells, and lower frequencies of CD57‐PD1+ CD8 and CD57‐PD1‐ CD8 T cells at 12‐month transplant (p <.05 for all). Conclusions: Children with obesity have distinct immunophenotypes that may influence the tailoring of immunosuppression. [ABSTRACT FROM AUTHOR]

Disorders of systemic metabolism can influence immunity. Individuals with obesity are known to have increased inflammation, increased risk to select autoimmune diseases, impaired response to several infections, and impaired vaccine response. For example, over the last decade, it has become clear that individuals with obesity have increased risk of morbidity and mortality from influenza infection. Unsurprisingly, this finding is also observed in the current COVID-19 pandemic: individuals with obesity, particularly severe obesity, have increased risk of poor outcomes from SARS-CoV-2 infection, including increased rates of hospitalization, ICU admission, mechanical ventilation, and death. Several studies have now demonstrated a critical role for T cells in the context of obesity-associated immune dysfunction in response to viral infection, and one mechanism for this may be altered T cell metabolism. Indeed, recent studies have shown that activated T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, both in vitro and in vivo following viral infection. For that reason, treatments that target abnormal immune cell metabolism in obesity may improve outcomes to viral infection. To that end, several recent studies have shown that use of the metabolic drug, metformin, can reverse abnormal T cell metabolism and restore T cell immunity, as well as survival, in response to viral infection. These findings will be discussed in detail here. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic demonstrates that obesity alone, independent of comorbidities, is a significant risk factor for severe outcomes from infection. This susceptibility mirrors a similar pattern with influenza infection; that is, obesity is a unique risk factor for increased morbidity and mortality. Therefore, it is critical to understand how obesity contributes to a reduced ability to respond to respiratory viral infections. Herein, we discuss human and animal studies with influenza infection and vaccination that show obesity impairs immunity. We cover several key mechanisms for the dysfunction. These mechanisms include systemic and cellular level changes that dysregulate immune cell metabolism and function in addition to how obesity promotes deficiencies in metabolites that control the resolution of inflammation and infection. Finally, we discuss major gaps in knowledge, particularly as they pertain to diet and mechanisms, which will drive future efforts to improve outcomes in response to respiratory viral infections in an increasingly obese population. [ABSTRACT FROM AUTHOR]

Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors. Importantly, previous studies have not evaluated whether graft-versus-leukemia (GVL) activity is preserved in donor T cells deficient for glycolysis. As a critical component affecting the clinical outcome, it is necessary to assess the anti-tumor activity following treatment with metabolic modulators in preclinical models. In the present study, we utilized T cells selectively deficient for glucose transporter 1 (Glut1T-KO), to examine the role of glycolysis exclusively in alloreactive T cells without off-targeting effects from antigen presenting cells and other cell types that are dependent on glycolysis. We demonstrated that transfer of Glut1T-KO T cells significantly improved acute GVHD outcomes through increased apoptotic rates, impaired expansion, and decreased proinflammatory cytokine production. In addition to impaired GVHD development, donor Glut1T-KO T cells mediated sufficient GVL activity to protect recipients from tumor development. A clinically relevant approach using donor T cells treated with a small molecule inhibitor of glycolysis, 2-Deoxy-D-glucose ex vivo, further demonstrated protection from tumor development. These findings indicate that treatment with glycolysis inhibitors prior to transplantation selectively eliminates alloreactive T cells, but spares non-alloreactive T cells including those that protect against tumor growth. The present study has established a definitive role for glycolysis in acute GVHD and demonstrated that acute GVHD can be selectively prevented through targeting glycolysis. [ABSTRACT FROM AUTHOR]

Obesity is an independent risk factor for morbidity and mortality in response to influenza infection. However, the underlying mechanisms by which obesity impairs immunity are unclear. Herein, we investigated the effects of diet‐induced obesity on pulmonary CD8+ T cell metabolism, cytokine production, and transcriptome as a potential mechanism of impairment during influenza virus infection in mice. Male C57BL/6J lean and obese mice were infected with sub‐lethal mouse‐adapted A/PR/8/34 influenza virus, generating a pulmonary anti‐viral and inflammatory response. Extracellular metabolic flux analyses revealed pulmonary CD8+ T cells from obese mice, compared with lean controls, had suppressed oxidative and glycolytic metabolism at day 10 post‐infection. Flow cytometry showed the impairment in pulmonary CD8+ T cell metabolism with obesity was independent of changes in glucose or fatty acid uptake, but concomitant with decreased CD8+GrB+IFNγ+ populations. Notably, the percent of pulmonary effector CD8+GrB+IFNγ+ T cells at day 10 post‐infection correlated positively with total CD8+ basal extracellular acidification rate and basal oxygen consumption rate. Finally, next‐generation RNA sequencing revealed complex and unique transcriptional regulation of sorted effector pulmonary CD8+CD44+ T cells from obese mice compared to lean mice following influenza infection. Collectively, the data suggest diet‐induced obesity increases influenza virus pathogenesis, in part, through CD8+ T cell‐mediated metabolic reprogramming and impaired effector CD8+ T cell function. [ABSTRACT FROM AUTHOR]

Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly via the leptin receptor, resulting in a largely pro-inflammatory phenotype. Understanding the role of adipose-tissue derived mediators in inflammation is critical to determining the pathophysiology of multiple obesity-associated diseases, such as type 2 diabetes, autoimmune disease, and infection. This review, therefore, focuses on the latest data regarding the role of leptin in modulating inflammation. [ABSTRACT FROM AUTHOR]

It is now well-established that the pathways that control lymphocyte metabolism and function are intimately linked, and changes in lymphocyte metabolism can influence and direct cellular function. Interestingly, a number of recent advances indicate that lymphocyte identity and metabolism is partially controlled via epigenetic regulation. Epigenetic mechanisms, such as changes in DNA methylation or histone acetylation, have been found to alter immune function and play a role in numerous chronic disease states. There are several enzymes that can mediate epigenetic changes; of particular interest are sirtuins, protein deacetylases that mediate adaptive responses to a variety of stresses (including calorie restriction and metabolic stress) and are now understood to play a significant role in immunity. This review will focus on recent advances in the understanding of how sirtuins affect the adaptive immune system. These pathways are of significant interest as therapeutic targets for the treatment of autoimmunity, cancer, and transplant tolerance. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Conclusion: Obesity-associated changes in T-cell metabolism are associated with impaired T-cell response to influenza, and are not reversed with weight loss. [ABSTRACT FROM AUTHOR]

Immune cell function and metabolism are closely linked. Many studies have now clearly demonstrated that alterations in cellular metabolism influence immune cell function and that, conversely, immune cell function determines the cellular metabolic state. Less well understood, however, are the effects of systemic metabolism or whole organism nutritional status on immune cell function and metabolism. Several studies have demonstrated that undernutrition is associated with immunosuppression, which leads to both increased susceptibility to infection and protection against several types of autoimmune disease, whereas overnutrition is associated with low-grade, chronic inflammation that increases the risk of metabolic and cardiovascular disease, promotes autoreactivity, and disrupts protective immunity. Here, we review the effects of nutritional status on immunity and highlight the effects of nutrition on circulating cytokines and immune cell populations in both human studies and mouse models. As T cells are critical members of the immune system, which direct overall immune response, we will focus this review on the influence of systemic nutritional status on T cell metabolism and function. Several cytokines and hormones have been identified which mediate the effects of nutrition on T cell metabolism and function through the expression and action of key regulatory signaling proteins. Understanding how T cells are sensitive to both inadequate and overabundant nutrients may enhance our ability to target immune cell metabolism and alter immunity in both malnutrition and obesity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Leptin is an adipokine that regulates body weight and appetite. It is also an inflammatory cytokine that influences immune reactivity and autoimmunity. Leptin levels are increased in obesity and are higher in women than in men. We aimed to determine whether leptin levels, independent of sex and body mass index ( BMI), are associated with thyroid autoimmunity. Design This study uses data from The Third National Health and Nutrition Examination Survey ( NHANES III) to test the association of leptin and thyroid autoimmunity, independent of BMI. Measurements Thyroid-stimulating hormone, thyroxine, antithyroid peroxidase ( TPO) antibodies and leptin levels were measured in 2902 men and 3280 women within the NHANES III population. BMI was calculated from height and weight. Results Women had significantly higher leptin levels and anti- TPO antibody titres than men. Correlation analyses demonstrated that leptin levels were associated with anti- TPO antibody levels in the total population, but when men and women were analysed separately, this association was lost. We then stratified men and women into obese ( BMI > 30) or nonobese ( BMI ≤ 30) subgroups and determined the association between leptin levels and anti- TPO antibody titres for each subgroup. Using regression analysis, we found that increased leptin levels correlated with thyroid autoantibodies in nonobese males, but not in obese males or in females. Conclusions Leptin levels correlated with thyroid autoantibody titres in nonobese males. This association was not found in females. Sex and body habitus should therefore be considered in studying the role of leptin in other autoimmune conditions. [ABSTRACT FROM AUTHOR]

Studies in transgenic murine models have provided insight into the complexity underlying inflammatory bowel disease (IBD), a disease hypothesized to result from an injurious immune response against intestinal microbiota. We recently developed a mouse model of IBD that phenotypically and histologically resembles human childhood-onset ulcerative colitis (UC), using mice that are genetically modified to be deficient in the cytokines TNF and IL-10 (“T/I” mice). Here we report the effects of early life onset of colon inflammation on growth and reproductive performance of T/I mice. T/I dams with colitis often failed to get pregnant or had small litters with pups that failed to thrive. Production was optimized by breeding double homozygous mutant T/I males to females homozygous mutant for TNF deficiency and heterozygous for deficiency of IL-10 (“T/I-het” dams) that were not susceptible to spontaneous colon inflammation. When born to healthy (T/I-het) dams, T/I pups initially gained weight similarly to wild type (WT) pups and to their non-colitis-susceptible T/I-het littermates. However, their growth curves diverged between 8 and 13 weeks, when most T/I mice had developed moderate to severe colitis. The observed growth failure in T/I mice occurred despite a significant increase in their food consumption and in the absence of protein loss in the stool. This was not due to TNF-induced anorexia or altered food consumption due to elevated leptin levels. Metabolic studies demonstrated increased consumption of oxygen and water and increased production of heat and CO2 in T/I mice compared to their T/I-het littermates, without differences in motor activity. Based on the clinical similarities of this early life onset model of IBD in T/I mice to human IBD, these results suggest that mechanisms previously hypothesized to explain growth failure in children with IBD require re-evaluation. The T/I mouse model may be useful for further investigation of such mechanisms and for development of therapies to prevent reproductive complications and/or growth failure in humans with IBD. [ABSTRACT FROM AUTHOR]

Nutritional status is critically important for immune cell function. While obesity is characterized by inflammation that promotes metabolic syndrome including cardiovascular disease and insulin resistance, malnutrition can result in immune cell defects and increased risk of mortality from infectious diseases. T cells play an important role in the immune adaptation to both obesity and malnutrition. T cells in obesity have been shown to have an early and critical role in inducing inflammation, accompanying the accumulation of inflammatory macrophages in obese adipose tissue, which are known to promote insulin resistance. How T cells are recruited to adipose tissue and activated in obesity is a topic of considerable interest. Conversely, T cell number is decreased in malnourished individuals, and T cells in the setting of malnutrition have decreased effector function and proliferative capacity. The adipokine leptin, which is secreted in proportion to adipocyte mass, may have a key role in mediating adipocyte-T cell interactions in both obesity and malnutrition, and has been shown to promote effector T cell function and metabolism while inhibiting regulatory T cell proliferation. Additionally, key molecular signals are involved in T cell metabolic adaptation during nutrient stress; among them, the metabolic regulator AMP kinase and the mammalian target of rapamycin have critical roles in regulating T cell number, function, and metabolism. In summary, understanding how T cell number and function are altered in obesity and malnutrition will lead to better understanding of and treatment for diseases where nutritional status determines clinical outcome. [ABSTRACT FROM AUTHOR]

T cell activation leads to dramatic shifts in cell metabolism to pro-tect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominandy ATP-generating pro-cesses, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally dis-tinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control im-mune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and func-tion to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis. [ABSTRACT FROM AUTHOR]

In their recent study, Nicholas et al. challenge the current dogma that T cell inflammation must be fueled by glycolysis and demonstrate a novel metabolic mechanism for Th17 inflammation in human type 2 diabetes mellitus (T2DM): a combination of increased environmental long-chain fatty acid metabolites coupled with decreased fatty acid oxidation. [ABSTRACT FROM AUTHOR]

Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease. [Display omitted] • ABL kinase allosteric inhibitors induce mitochondrial-mediated apoptosis • HMG-CoA reductase inactivation synergizes with ABL allosteric inhibitors to induce apoptosis • Isoprenoid pathway rescues cell survival upon cotreatment with statin and ABL001 • Cotreatment of ABL001 and simvastatin decreases metastases in mouse models Metabolic reprogramming in tumors is an adaptation that generates vulnerabilities that can be exploited for developing new therapies. Here Luttman et al. identify synergism between ABL allosteric inhibitors and lipophilic statins to impair metastatic lung cancer cell outgrowth and colonization, leading to increased survival in mouse models of advanced disease. [ABSTRACT FROM AUTHOR]

The article discusses a study by M. Tauber and colleagues, published within the issue, on whether treatment of Prader-Willi syndrome (PWS) with oxytocin improves poor feeding and social behaviors in infants. Topics include characteristics of PWS, connectivity of the right superior orbitofrontal network after treatment with oxytocin, and finding on early administration of oxytocin to infants with PWS.

CD4 T cells play a major role to orchestrate the immune response. Upon activation, CD4 T cells differentiate into effector T cell (Teff) or regulatory T cell (Treg) subsets that promote or suppress the immune response, respectively. Along with these unique immunological roles, CD4 T cell subsets have specific metabolic requirements and programs that can influence the immune response. We therefore examined the metabolite levels of Teff and Treg in detail. Surprisingly, the metabolite showing the largest difference between Teff and Treg was serotonin (5-HT), revealing a potentially distinct role for serotonin in CD4 T cell function. 5-HT is well known as a neurotransmitter and recently has been recognized to play a role in the immune response; however, little is known about the immune cell type-specific expression of the serotonergic machinery and receptors. We therefore examined the serotonergic-related machinery in Teff and Treg and found differential expression of the serotonin transporter SERT and 5-HT1a and 5-HT2 receptors. We also found that Treg express tryptophan hydroxylase, which converts tryptophan to serotonin, suggesting for the first time that Treg synthesize serotonin. Our results in this study expand the potential immunomodulatory role of serotonin in CD4 T cell biology and could ultimately aid the development of novel immunomodulatory targets for treatment of autoimmune and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-γ-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts. [ABSTRACT FROM AUTHOR]

Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction. [ABSTRACT FROM AUTHOR]

Immune responses are highly energy-dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. Although it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show in this study that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show that leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell intrinsic and specific to activated effector T cells, as naive T cells and regulatory T cells did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Obesity dysregulates immunity to influenza infection. Therefore, there is a critical need to investigate how obesity impairs immunity and to establish therapeutic approaches that mitigate the impact of increased adiposity. One mechanism by which obesity may alter immune responses is through changes in cellular metabolism., Methods: We studied inflammation and cellular metabolism of peripheral blood mononuclear cells (PBMCs) isolated from individuals with obesity relative to lean controls. We also investigated if impairments to PBMC metabolism were reversible upon short-term weight loss following bariatric surgery., Results: Obesity was associated with systemic inflammation and poor inflammation resolution. Unstimulated PBMCs from participants with obesity had lower oxidative metabolism and adenosine triphosphate (ATP) production compared to PBMCs from lean controls. PBMC secretome analyses showed that ex vivo stimulation with A/Cal/7/2009 H1N1 influenza led to a notable increase in IL-6 with obesity. Short-term weight loss via bariatric surgery improved biomarkers of systemic metabolism but did not improve markers of inflammation resolution, PBMC metabolism, or the PBMC secretome., Conclusions: These results show that obesity drives a signature of impaired PBMC metabolism, which may be due to persistent inflammation. PBMC metabolism was not reversed after short-term weight loss despite improvements in measures of systemic metabolism., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity is an independent risk factor for morbidity and mortality in response to influenza infection. However, the underlying mechanisms by which obesity impairs immunity are unclear. Herein, we investigated the effects of diet-induced obesity on pulmonary CD8 + T cell metabolism, cytokine production, and transcriptome as a potential mechanism of impairment during influenza virus infection in mice. Male C57BL/6J lean and obese mice were infected with sub-lethal mouse-adapted A/PR/8/34 influenza virus, generating a pulmonary anti-viral and inflammatory response. Extracellular metabolic flux analyses revealed pulmonary CD8 + T cells from obese mice, compared with lean controls, had suppressed oxidative and glycolytic metabolism at day 10 post-infection. Flow cytometry showed the impairment in pulmonary CD8 + T cell metabolism with obesity was independent of changes in glucose or fatty acid uptake, but concomitant with decreased CD8 + GrB + IFNγ + populations. Notably, the percent of pulmonary effector CD8 + GrB + IFNγ + T cells at day 10 post-infection correlated positively with total CD8 + basal extracellular acidification rate and basal oxygen consumption rate. Finally, next-generation RNA sequencing revealed complex and unique transcriptional regulation of sorted effector pulmonary CD8 + CD44 + T cells from obese mice compared to lean mice following influenza infection. Collectively, the data suggest diet-induced obesity increases influenza virus pathogenesis, in part, through CD8 + T cell-mediated metabolic reprogramming and impaired effector CD8 + T cell function., (©2021 Society for Leukocyte Biology.)

Although obesity can promote cancer, it may also increase immunotherapy efficacy in what has been termed the obesity-immunotherapy paradox. Mechanisms of this effect are unclear, although obesity alters key inflammatory cytokines and can promote an inflammatory state that may modify tumor-infiltrating lymphocytes and tumor-associated macrophage populations. To identify mechanisms by which obesity affects antitumor immunity, we examined changes in cell populations and the role of the proinflammatory adipokine leptin in immunotherapy. Single-cell RNAseq demonstrated that obesity decreased tumor-infiltrating lymphocyte frequencies, and flow cytometry confirmed altered macrophage phenotypes with lower expression of inducible NO synthase and MHC class II in tumors of obese animals. When treated with anti-programmed cell death protein 1 (PD-1) Abs, however, obese mice had a greater absolute decrease in tumor burden than lean mice and a repolarization of the macrophages to inflammatory M1-like phenotypes. Mechanistically, leptin is a proinflammatory adipokine that is induced in obesity and may mediate enhanced antitumor immunity in obesity. To directly test the effect of leptin on tumor growth and antitumor immunity, we treated lean mice with leptin and observed tumors over time. Treatment with leptin, acute or chronic, was sufficient to enhance antitumor efficacy similar to anti-PD-1 checkpoint therapy. Further, leptin and anti-PD-1 cotreatment may enhance antitumor effects consistent with an increase in M1-like tumor-associated macrophage frequency compared with non-leptin-treated mice. These data demonstrate that obesity has dual effects in cancer through promotion of tumor growth while simultaneously enhancing antitumor immunity through leptin-mediated macrophage reprogramming., (Copyright © 2021 by The American Association of Immunologists, Inc.)

In this issue of Immunity, Šestan et al. (2018) show that viral-induced inflammation leads to insulin resistance in skeletal muscle, followed by compensatory hyperinsulinemia, which promotes the anti-viral effector response of CD8 + T cells. Interestingly, this leads to persistent glucose intolerance and the progression of type 2 diabetes in pre-diabetic animals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

CD4 + effector T cells (T eff cells) and regulatory T cells (T reg 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 eff cell proliferation and inflammatory function, the mechanisms that regulate T reg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote T reg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired T reg 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 reg 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 reg cells., Competing Interests: The authors declare no competing financial interests.

T cell activation leads to engagement of cellular metabolic pathways necessary to support cell proliferation and function. However, our understanding of the signal transduction pathways that regulate metabolism and their impact on T cell function remains limited. The liver kinase B1 (LKB1) is a serine/threonine kinase that links cellular metabolism with cell growth and proliferation. In this study, we demonstrate that LKB1 is a critical regulator of T cell development, viability, activation, and metabolism. T cell-specific ablation of the gene that encodes LKB1 resulted in blocked thymocyte development and a reduction in peripheral T cells. LKB1-deficient T cells exhibited defects in cell proliferation and viability and altered glycolytic and lipid metabolism. Interestingly, loss of LKB1 promoted increased T cell activation and inflammatory cytokine production by both CD4(+) and CD8(+) T cells. Activation of the AMP-activated protein kinase (AMPK) was decreased in LKB1-deficient T cells. AMPK was found to mediate a subset of LKB1 functions in T lymphocytes, as mice lacking the α1 subunit of AMPK displayed similar defects in T cell activation, metabolism, and inflammatory cytokine production, but normal T cell development and peripheral T cell homeostasis. LKB1- and AMPKα1-deficient T cells each displayed elevated mammalian target of rapamycin complex 1 signaling and IFN-γ production that could be reversed by rapamycin treatment. Our data highlight a central role for LKB1 in T cell activation, viability, and metabolism and suggest that LKB1-AMPK signaling negatively regulates T cell effector function through regulation of mammalian target of rapamycin activity.

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.

Lymphocytes require glucose uptake and metabolism for normal survival and function. The signals that regulate the expression and localization of glucose transporter 1 (Glut1) to allow glucose uptake in T cells are now beginning to be understood. Resting T cells require extracellular signals, such as cytokines, hormones, and growth factors, or low-level TCR stimulation to take up adequate glucose to maintain housekeeping functions. In the absence of extrinsic signals, resting T cells internalize and degrade Glut1 and cannot maintain viability. Activated T cells have dramatically increased metabolic requirements to support the energy and biosynthetic needs necessary for growth, proliferation, and effector function. In particular, glucose metabolism and aerobic glycolysis fuel this demand. Therefore, activation of T cells causes a large increase in Glut1 expression and surface localization. If glucose uptake is limited, glycolytic flux decreases to a level that no longer sustains viability, and proapoptotic Bcl-2 family members become activated, promoting cell death. However, excessive glucose uptake can promote hyperactive immune responses and possible immune pathology. Tight regulation of glucose uptake is required to maintain immune homeostasis, and understanding of these metabolic pathways may lead to therapeutic strategies to target some forms of cancer or autoimmunity.