Metabolic regulation of T lymphocytes.

T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune 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 function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.

Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression.

CD4+ effector T cells (Teff cells) and regulatory T cells (Treg 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 Teff cell proliferation and inflammatory function, the mechanisms that regulate Treg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote Treg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired Treg 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 Treg 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 Treg cells.

Viral Infection "Interferes" with Glucose Tolerance.

In this issue of Immunity, Sestan 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.

Type I interferon signaling and peroxisomal dysfunction contribute to enhanced inflammatory cytokine production in Irgm1-deficient macrophages.

The human IRGM gene has been linked to inflammatory diseases including sepsis and Crohn's disease. Decreased expression of human IRGM, or of the mouse orthologues Irgm1 and Irgm2, leads to increased production of a number of inflammatory chemokines and cytokines in vivo and/or in cultured macrophages. Prior work has indicated that increased cytokine production is instigated by metabolic alterations and by changes in mitochondrial homeostasis; however, a comprehensive mechanism has not been elucidated. In the studies presented here, RNA deep sequencing and quantitative PCR were used to show that increases in cytokine production, as well as most changes in the transcriptional profile of Irgm1-/- bone marrow-derived macrophages (BMM), are dependent on increased type I IFN production seen in those cells. Metabolic alterations that drive increased cytokines in Irgm1-/- BMM - specifically increases in glycolysis and increased accumulation of acyl-carnitines - were unaffected by quenching type I IFN signaling. Dysregulation of peroxisomal homeostasis was identified as a novel upstream pathway that governs type I IFN production and inflammatory cytokine production. Collectively, these results enhance our understanding of the complex biochemical changes that are triggered by lack of Irgm1 and contribute to inflammatory disease seen with Irgm1-deficiency.

Metformin as a Therapeutic Agent for Obesity-Associated Immune Dysfunction.

Obesity is associated with impaired immune function, characterized by inflammation, and leading to poor response to infection, impaired vaccine response, increased susceptibility to autoimmune disease, and increased risk of cancer and cancer mortality. Worse, there is evidence that weight loss alone may be insufficient to reverse the immune dysfunction caused by obesity. It is therefore critically important to identify alternative therapeutic approaches to decrease the negative effects of obesity-associated inflammation. In this article, we will review evidence that the antidiabetic drug metformin may be considered as a therapeutic agent for obesity-associated immune dysfunction. Metformin has immunomodulatory effects, stimulating or suppressing the immune response in both a cell-specific and disease-specific manner. Although the mechanism of action of metformin on the immune system remains to be fully elucidated, there is strong evidence that metformin enters select immune cells and disrupts electron transport, leading to both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent effects on immune cell differentiation and cytokine production. These effects of metformin on immune cells have been shown to improve immune responses to infection, autoimmunity, and cancer.

Metformin use associated with lower rate of hospitalization for influenza in individuals with diabetes.

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.

Obesity Dysregulates the Immune Response to Influenza Infection and Vaccination Through Metabolic and Inflammatory Mechanisms.

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.

Leptin Augments Antitumor Immunity in Obesity by Repolarizing Tumor-Associated Macrophages.

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.

Inflammation and Metabolism of Influenza-Stimulated Peripheral Blood Mononuclear Cells From Adults With Obesity Following Bariatric Surgery.

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.

Malnutrition and immune cell subsets in children undergoing kidney transplantation.

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.

Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity.

BACKGROUND: Obesity is associated with impaired primary and secondary immune responses to influenza infection, with T cells playing a critical role. T-cell function is highly influenced by the cellular metabolic state; however, it remains unknown how altered systemic metabolism in obesity alters T-cell metabolism and function to influence immune response. Our objective was to identify the altered cellular metabolic state of T cells from obese mice so that we may target T-cell metabolism to improve immune response to infection. METHODS: Mice were fed normal chow or high-fat diet for 18-19 weeks. Changes in T-cell populations were analyzed in both adipose tissue and spleens using flow cytometry. Splenic T cells were further analyzed for nutrient uptake and extracellular metabolic flux. As changes in T-cell mitochondrial oxidation were observed in obesity, obese mice were treated with metformin for 6 weeks and compared to lean control mice or obese mice undergoing weight loss through diet switch; immunity was measured by survival to influenza infection. RESULTS: We found changes in T-cell populations in adipose tissue of high-fat diet-induced obese mice, characterized by decreased proportions of Treg cells and increased proportions of CD8+ T cells. Activated CD4+ T cells from obese mice had increased glucose uptake and oxygen consumption rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose. Treatment of isolated CD4+ T cells with metformin was found to inhibit OCR in vitro and alter the expression of several activation markers. Last, treatment of obese mice with metformin, but not weight loss, was able to improve survival to influenza in obesity. CONCLUSIONS: T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, which can be targeted to improve survival against influenza infection.

Obesity-Induced Changes in T-Cell Metabolism Are Associated With Impaired Memory T-Cell Response to Influenza and Are Not Reversed With Weight Loss.

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.

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.

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.

Nutritional effects on T-cell immunometabolism.

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.

Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.

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.

Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.

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.

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.

The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next generation sequencing to have the same heterozygous mutation in an essential donor splice site of PIK3R1 (NM_181523.2:c.1425 + 1G > A) found in three prior reports. All four had the Hyper IgM syndrome, lymphadenopathy and short stature, and one also had SHORT syndrome. They were investigated with in vitro immune studies, RT-PCR, and immunoblotting studies of the mutation's effect on mTOR pathway signaling. All patients had very low percentages of memory B cells and class-switched memory B cells and reduced numbers of naïve CD4+ and CD8+ T cells. RT-PCR confirmed the presence of both an abnormal 273 base-pair (bp) size and a normal 399 bp size band in the patient and only the normal band was present in the parents. Following anti-CD40 stimulation, patient's EBV-B cells displayed higher levels of S6 phosphorylation (mTOR complex 1 dependent event), Akt phosphorylation at serine 473 (mTOR complex 2 dependent event), and Akt phosphorylation at threonine 308 (PI3K/PDK1 dependent event) than controls, suggesting elevated mTOR signaling downstream of CD40. These observations suggest that amino acids 435-474 in PIK3R1 are important for its stability and also its ability to restrain PI3K activity. Deletion of Exon 11 leads to constitutive activation of PI3K signaling. This is the first report of this mutation and immunologic abnormalities in SHORT syndrome.

Increased leptin levels correlate with thyroid autoantibodies in nonobese males.

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.

Leptin metabolically licenses T cells for activation to link nutrition and immunity.

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.

Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function.

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.