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. Author manuscript; available in PMC: 2019 Mar 9.
Published in final edited form as: J Bioenerg Biomembr. 2018 Feb 6;50(3):223–229. doi: 10.1007/s10863-018-9744-1

O-GlcNAc: a novel regulator of immunometabolism

Miranda Machacek 1,2, Chad Slawson 2, Patrick E Fields 1,✉
PMCID: PMC6408937  NIHMSID: NIHMS1015537  PMID: 29404877

Abstract

The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4+ T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. However, when T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation. The mechanisms by which metabolic changes influence function in CD4+ T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), dynamically cycles on and off of intracellular proteins as cells respond to their environment and flux through metabolic pathways changes. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected. Thus, O-GlcNAc is critically poised at the nexus of cellular metabolism and function. This review highlights the intra- and extracellular metabolic factors that influence CD4+ T cell activation and differentiation and how O-GlcNAc regulates these processes. We also propose areas of future research that may illuminate O-GlcNAc’s role in the plasticity and pathogenicity of CD4+ T cells and uncover new potential therapeutic targets.

Keywords: O-GlcNAc, T cells, Metabolic regulation, Inflammation

Introduction

The immune system is composed of a host of widely distributed and extremely dynamic cells capable of expanding and contracting rapidly in response to a myriad of microbial and environmental threats. Within this complex network of cells, CD4+ T cells orchestrate the adaptive immune response’s elimination of a pathogen in a highly specific manner. Among their many functions, CD4+ T cells dictate which class of immunoglobulin is expressed by B cells, enhance phagocytic function of innate immune cells like macrophages, and themselves differentiate into various effector cells specialized to eliminate a class of pathogens (Geginat et al. 2013). Due to the dynamic and highly proliferative nature of CD4+ T cells, a fascinating question about their biology has emerged: How can metabolism, another highly dynamic cellular process, influence their function? Indeed, the burgeoning field of immunometabolism seeks to understand how the metabolic state of immune cells alters function and may be targeted or manipulated for therapeutic purposes. This review will address the ways metabolic pathways influence CD4+ T cell function and how a post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), whose cycling is dependent on input from multiple metabolic pathways, is critical for CD4+ T cell function. We will also offer our perspective on the intriguing possibilities of how O-GlcNAc plays a role in CD4+ T cell function and inflammatory diseases.

Distinct metabolic programs are critical during T cell activation

In lymph nodes, naïve CD4+ T cells are activated by antigen presenting cells (APC), such as dendritic cells, expressing major histocompatibility complex II (MHC II) loaded with an antigenic peptide on their cell surface. Activation requires recognition of this peptide-MHC II complex by the clonally unique T cell receptor (TCR). In addition to this first signal, a second signal is required to stimulate optimal proliferation of that particular T cell receptor-bearing clone. This second signal is provided by a co-stimulatory molecule, such as CD28. With these two signals, a T cell is now activated to respond specifically to the pathogen loaded onto the MHC II complex. Activation triggers massive proliferation of the T cell and thus requires a tremendous influx of metabolites to sustain initial cell growth and subsequent multiple cellular divisions. Not surprisingly, T cell activation triggers a complete switch in metabolic programs.

Naïve CD4+ T cells switch from relying primarily on oxidative phosphorylation for their metabolic needs to aerobic glycolysis and glutaminolytic programs. With this switch comes an influx of metabolites capable of fueling cell growth and proliferation. For example, early studies identified a sudden influx of glucose into activated T cells (Loos and Roos 1973). This initial observation has been further expanded upon by studies showing that activation triggers the upregulation of GLUT1 on the T cell surface. This upregulation is mediated through the CD28 co-stimulatory signaling pathway that engages the PI3K-AKT signaling cascade as well as MYC-mediated transcriptional activation of glycolytic genes (Frauwirth et al. 2002; Rathmell et al. 2003; Wang et al. 2011). In addition to increased glucose, activated T cells also require more amino acids. TCR and CD28 engagement both increase expression of amino acid transporters, particularly those needed for the import of leucine and glutamine (Sinclair et al. 2013; Nakaya et al. 2014). Activated T cells have a very strong requirement for glutamine as an energy source (Griffiths and Keast 1990)—increasing uptake of this particular amino acid ten times more than any other amino acid (Jones and Thompson 2007). Besides being necessary for increased protein translation, glutamine is a versatile building block for many other cellular metabolites, including nucleotides via the de novo synthetic pathway and serving as an anaplerotic source of oxaloacetate (OAA) in the TCA cycle. By replenishing OAA, citrate can be continuously generated and transported out of the mitochondria where it is converted to acetyl CoA, the foundational building block for fatty acid and cholesterol synthesis. Essentially, conversion of gluta-mine to acetyl CoA provides the building block required for increased fatty acid synthesis during T cell activation. This step is critical since activated effector T cells favor de novo synthesis rather than exogenous uptake of fatty acids (Wang et al. 2011). Overall, T cell activation induces major metabolic shifts, resulting in the cell switching from oxidative phosphorylation and fatty acid oxidation for its energetic needs to aerobic glycolysis, glutaminolysis, increased pentose phosphate pathway flux, and de novo lipid generation. This substantial change in metabolism is thought to be required to meet the cell’s new, increased metabolic demands. Importantly, these metabolic pathways all produce substrates required in the hexosamine biosynthetic pathway for UDP-GlcNAc synthesis and thus protein O-GlcNAcylation (Fig. 1).

Fig. 1.

Fig. 1

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T cell activation induces cell surface expression of GLUT1 and amino acid transporters, facilitating uptake of glucose and glutamine. This enhanced nutrient state provides substrates that directly feed into the hexosamine biosynthetic pathway (HBP), driving increased UDP-GlcNAc synthesis and protein O-GlcNAcylation by O-GlcNAc transferase (OGT).

Intrinsic and external metabolic factors are required for specific CD4+ T cell differentiation and function

In addition to providing the stimuli needed for T cell activation, cytokines secreted by the antigen-presenting cell during activation will direct CD4+ T cell differentiation into one of at least six classes of specialized effectors. In this review, we focus on four of the “main” classes of these effectors: 1) T helper 1 (Th1), which target intracellular and viral pathogens; 2) Th2, which target helminths; 3) Th17, which target fungal and extracellular bacteria; and 4) inducible regulatory T cells (iTregs), which have an opposing function in decreasing the inflammatory immune response (Fig. 2). Th1, Th2, and Th17 are often categorized as “effectors” due to their vital function in eliminating specific classes of pathogens, while regulatory T cells serve to “soothe” inflammation and thus can be considered a special class of effector T cell. Additionally, effectors are inappropriately increased in situations of autoimmunity (Th1 and Th17) and allergies (Th2). Based on their varied functions, it is not surprising that distinct metabolic pathways are also critical for the differentiation of specific T cell subsets. Th1, Th2, Th17 primarily utilize glycolysis and glutaminolysis for their energy needs and absolutely require GLUT1, while iTregs continue to utilize oxidative phosphorylation to meet their energetic needs and are unaffected by GLUT1 deficiency (Michalek et al. 2011; Macintyre et al. 2014). Instead, inhibition of fatty acid catabolism blunts iTreg differentiation, and increased AMPK signaling (such as that induced by metformin) serves to increase iTreg differentiation (Michalek et al. 2011). A glycolytic enzyme recently found to be integral to CD4+ T cell differentiation is pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl CoA, the major building block for fatty acid biosynthesis. Pyruvate dehydrogenase kinase 1 (PDHK1) inhibits PDH activity and enhances glycolytic flux. PDHK1 is selectively up-regulated in Th17, but not in Th1 or iTregs. Inhibition of PDHK1 decreases Th17 differentiation, demonstrating a glycolytic dependence for Th17 cells (Gerriets et al. 2015).

Fig. 2.

Fig. 2

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Cytokines secreted by antigen presenting cells (APC) induce signaling through STAT proteins, which upregulate a lineage-defining transcription factor. This “master” transcription factor then induces transcription of cytokines that carry out the specialized function of the T cell. Th1, Th2, and Th17 have effector functions in eliminating specific classes of pathogens, but over-activity can lead to disease. Inducible Tregs serve an opposing function in diminishing effector T cell responses.

Besides metabolizing glucose differently, differential components of the amino-acid sensing mTOR signaling pathway are specifically required by different T cell subsets. Loss of the entire mTOR complex leads to loss of differentiation into all effector lineages except for iTreg, whose differentiation remains unaffected. This underscores the iTreg reliance on AMPK signaling, which normally serves to inhibit mTOR activity (Delgoffe et al. 2009). mTOR is composed of two different complexes (mTORC1 and mTORC2), each with its own distinct regulation and function (Wullschleger et al. 2006). Interestingly, mTORC1 and Rheb, the GTP-binding protein that activates mTORC1, are required for Th1 and Th17 differentiation, while mTORC2 is needed for Th2 differentiation (Delgoffe et al. 2011). T cell effectors also have a differential requirement for fatty acid metabolic pathways. Specifically, Th17 cells require acetyl CoA carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis, while iTreg differentiation is unaffected by ACC knockout (Berod et al. 2014). Further demonstrating a necessity for fatty acid anabolism versus catabolism in iTregs, ACC is upregulated in obese mice and human memory CD4+ T cells. The enzyme also provides fatty acid ligands that enhance retinoic acid receptor-related orphan receptor t isoform (RORγt), the line-age-defining, “master” transcription factor for Th17 cells, critical for their activity and IL-17 production (Endo et al. 2015). Increased ACC activity also increases substrates for cholesterol metabolism. Specific oxysterols derived from cholesterol metabolism are potent activating ligands for RORγt, increasing RORγt transcriptional activity, and thus Th17 differentiation (Soroosh et al. 2014; Santori et al. 2015).

In addition to intrinsic metabolic pathways, various extrinsic metabolic and environmental signals heavily influence CD4+ T cell differentiation, particularly along the Th17 and iTreg axis. As an example, sites of inflammation are frequently hypoxic. Accordingly, hypoxia inducible factor-1α (HIF-1α) has been demonstrated to be essential in upregulating glycolytic genes in Th17 cells (Shi et al. 2011). HIF-1α also directly enhances transcription of RORγt, while actively targeting forkhead box P3 (Foxp3), the iTreg master transcription factor, for ubiquitin-mediated degradation (Dang et al. 2011). Hormones also exogenously regulate CD4+ T cell differentiation. Many autoimmune diseases exhibit sexual dimorphism with increased incidence in females. Androgens act as ligands for different peroxisome proliferator activated receptor (PPAR) types. In human CD4+ T cells, androgens upregulate PPARα which suppresses Th1 and interferon-γ (IFNγ) production, while selectively enhancing IL-17 secretion (Zhang et al. 2012). Human male CD4+ T cells with PPARα knockout secreted IFNγ similarly to female CD4+ T cells (Zhang et al. 2012). Other hormonal influences on T cell differentiation include leptin, a hormone released to indicate satiety. Leptin signals through signal transducer and activator of transcription 3 (STAT3), which is the major STAT required for enhancing RORγt and IL-17 transcription in Th17 cells. Fittingly, leptin receptor expression is required for Th17 differentiation (Reis et al. 2015) and is yet another signaling pathway found to upregulate glycolytic metabolism via HIF-1α (Gerriets et al. 2016). On the stranger, yet fascinating side, disrupted circadian rhythms have been shown to increase Th17 differentiation (Yu et al. 2013). Clock proteins rhythmically inhibit NFIL3 (nuclear factor, IL-3 regulated) expression, which ordinarily represses RORγt transcription. However, when mice are subjected to altered light/dark cycles to mimic jet lag, increased inhibition of NFIL3 by the Rev-erbα clock protein results in increased Th17 differentiation (Yu et al. 2013). Finally, modestly elevated NaCl concentrations induce activity of serum glucocorticoid kinase 1 (SGK1), which stabilizes IL-23 receptor expression, important for locking in a pathogenic Th17 phenotype (Wu et al. 2013; Kleinewietfeld et al. 2013). Knockout of SGK1 results in decreased Th1- and Th17-driven autoimmune inflammation in a mouse model of multiple sclerosis (EAE, experimental autoimmune encephalomyelitis) due to a loss of Th17 stability. This effect was completely reversed by feeding the mice a high-salt diet (Wu et al. 2013; Kleinewietfeld et al. 2013). Recently, SGK1 regulation of the Th1 vs Th2 axis was clarified (Heikamp et al. 2014). Activation of SGK1 occurs downstream of mTORC2, which is required for Th2 differentiation (Delgoffe et al. 2011). Accordingly, knockout of SGK1 ameliorated a Th2-mediated allergic lung inflammation, suggesting importance in Th2 rather than Th1 differentiation (Heikamp et al. 2014).

Finally, bacterial metabolic by-products unique to the gut can regulate CD4+ T cell differentiation. The gut is considered a distinct immunological site due to the constant presence of commensal and potentially pathogenic bacteria, which the immune system must carefully discriminate between to appropriately balance inflammation and tolerance. Proper balance of the Th17 versus iTreg axis is of particular importance in the gut, and thus much research has gone into exploring mechanisms regulating this balance. Specific strains of bacteria, the segmented filamentous bacteria, are required to induce gut resident Th17 cells (Ivanov et al. 2009). Fatty acids derived from the microbiota critically regulate the balance of iTreg and Th17 in the gut. Short chain fatty acids, such as butyrate, induce iTregs, while long chain fatty acids induce Th1 and/or Th17 differentiation sufficient to enhance autoimmune EAE (Haghikia et al. 2015). Additionally, tryptophan derivatives derived from gut bacteria promote iTreg differentiation and quell EAE autoimmune inflammation (Yan et al. 2010).

O-GlcNAcylation is required for T cell activation

A less well known, yet critical metabolic pathway is the hexosamine biosynthetic pathway (HBP). Incorporating metabolites from carbohydrate, amino acid, fatty acid, and nucleic acid pathways, the HBP results in the synthesis of UDP-GlcNAc, the substrate used by O-GlcNAc transferase (OGT) to O-GlcNAcylate proteins. As the concentration of UDP-GlcNAc rises, more substrate is available and O-GlcNAcylation increases (Kreppel and Hart 1999). Glutamine is a substrate required by GFAT (glucose:fructose-6-phosphate amidotransferase), the rate-limiting enzyme in the HBP. Thus, when glucose and glutamine influx rapidly increase during T cell activation, UDP-GlcNAc levels and subsequent O-GlcNAcylation can also increase (Swamy et al. 2016). This effect was first observed during the initial identification of intracellular glycosylation with O-GlcNAc in activated Jurkat T cells (Kearse 1991). T cell activation rapidly induced distinct changes in the population of O-GlcNAcylated nuclear and cytoplasmic proteins. O-GlcNAcylation is essential during T cell activation, since siRNA knock-down of OGT significantly hinders T cell activation (Golks et al. 2007). This effect is due in part because O-GlcNAcylation of NF-κB and NFAT, transcription factors essential for IL-2 gene transcription which drives the proliferative response, is required for their translocation from the cytoplasm to the nucleus (Golks et al. 2007; Ramakrishnan et al. 2013). Interestingly, O-GlcNAcylation of NF-κB was induced under specific conditions such as hyper-glycemia, suggesting a link between increased O-GlcNAcylation and exaggerated production of inflammatory cytokines such as IFNγ under its transcriptional control (Ramakrishnan et al. 2013). O-GlcNAcylation is required during activation in primary human T cells as well (Lund et al. 2016). A specific requirement for OGT but not OGA function was identified, which was linked to OGT localization to a cluster of kinases immediately downstream of TCR signaling (Lund et al. 2016). This study also identified several new O-GlcNAcylated proteins among these proximal kinases, such as LCK and ZAP-70, which are key players in transmitting the TCR signal (Lund et al. 2016). Identification of OGT-mediated modification of proteins at the beginning of the TCR signaling pathway provides a possible explanation for why O-GlcNAcylation levels rise so rapidly after activation before nutrient transporters have had a chance to demonstrably increase nutrient flux. Taken together, the data strongly support O-GlcNAc as a critical regulator of activation signals needed for T cell proliferation.

O-GlcNAc in T cell mediated diseases

The role of O-GlcNAc in CD4+ T cell differentiation is poorly understood, but several studies hint at a role for this modification in regulating T cell effectors in autoimmune diseases. The X-linked OGT gene is hypomethylated in T cells from female patients with systemic lupus erythematosus, an auto-immune disease with a high prevalence especially in females mediated in part by Th1 and Th17 cells (Hewagama et al. 2013). Additionally, miRNA15-b targeting of OGT transcripts was recently found to be down-regulated in T cells from multiple sclerosis patients, resulting in increased Th17 differentiation (Liu et al. 2017). ELF-1, a transcription factor for the TCR ζ chain gene, requires O-GlcNAcylation and phosphorylation to translocate from the cytoplasm to the nucleus. Decreased O-GlcNAcylation was found on ELF-1 in SLE patients and led to a decrease in TCR ζ chain levels on their T cells (Juang et al. 2002; Tsokos et al. 2003). Interestingly, restoring appropriate levels of TCR ζ chain was sufficient to ameliorate T effector cell dysfunction (Nambiar et al. 2003). These observations suggest dysregulated O-GlcNAcylation results in aberrant CD4+ T cell effector function. Particularly, dysregulated cycling of O-GlcNAc due to changes in OGT levels may have a role in enhancing pro-inflammatory T effector function in the context of autoimmunity. Finally, O-GlcNAcylation is essential for T cell malignancy, since T cell specific OGT knockout prevented malignant transformation of PTEN-knockout thymocytes (Swamy et al. 2016). However, this is likely due more to O-GlcNAc’s essential role in organizing the mitotic spindle and regulating cellular division than in regulating T cell cancers specifically (Tan et al. 2013; Slawson et al. 2005; Lanza et al. 2016). Many unanswered questions remain in our understanding of how O-GlcNAc regulates CD4+ T cell differentiation and how aberrant O-GlcNAcylation may promote inflammatory diseases.

Future perspectives

As a post-translational protein modification exquisitely sensitive to changes in metabolic state and environmental factors, O-GlcNAc seems poised as a major regulator of T cell function. Besides a clear role in activation, what other functions might O-GlcNAc have in CD4+ T cell biology and how might aberrant O-GlcNAcylation contribute to T cell mediated disease? We propose three areas in which the dynamic nature of T cells and their surrounding environment might intersect with the dynamic nature of O-GlcNAc.

First, a fascinating feature of CD4+ T cell subsets is their substantial plasticity. For example, Th17 cells have two distinct functional states—a non-pathogenic state in which cells secrete both IL-17 and IL-10, an anti-inflammatory cytokine typical of iTregs, and a pathogenic state, in which cells secrete both IL-17 and IFNγ, the classical Th1 cytokine (Boniface et al. 2010; Lee et al. 2009). This dual Th17/Th1-like phenotype is linked to the pathogenesis of many autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, and type 1 diabetes (Lee et al. 2009; Ghoreschi et al. 2010; Martin-Orozco et al. 2009). Non-pathogenic Th17 convert to a pathogenic state when injected into a non-obese diabetic mouse model of type 1 diabetes, suggesting that abnormal metabolism may be involved in this conversion (Martin-Orozco et al. 2009). Further supporting a role for metabolic factors, the saturated to unsaturated fatty acid ratio in Th17 cells is critical for pathogenicity. Increased saturated fatty acids due to a decreased expression of CD5L, a protein whose only previously known function was in macrophages, drove pathogenicity by creating ligands that specifically enhanced RORγt transcriptional activity at the IL-17 locus, while decreasing IL-10 transcriptional activity (Wang et al. 2015). In future studies, it would be interesting to examine how O-GlcNAc might regulate critical nodes that shift plasticity, such as CD5L, and ways this could be altered therapeutically as a molecular switch of cellular states.

Second, pro-inflammatory Th1 and Th17 cells critically drive many autoimmune diseases. As mentioned previously, dysregulated OGT levels have been implicated in promoting inflammatory T cells in multiple sclerosis and systemic lupus erythematosus (SLE) (Hewagama et al. 2013; Liu et al. 2017). Additionally, disruptions in metabolic pathways of T cells have been implicated in autoimmune inflammation, which could lead to increased shunting of metabolites into the hexosamine biosynthetic pathway, fueling O-GlcNAcylation. For example, inappropriate, chronic stimulation of the PI3K-AKT-mTOR signaling pathway leads to the accumulation of inflammatory Th17 cells in SLE (Koga et al. 2014). Synovial infiltrating inflammatory T cells in rheumatoid arthritis have decreased glycolytic flux at the rate-limiting step, shunting substrates towards the pentose phosphate pathway (PPP) (Shen et al. 2017). Increased PPP flux increases production of NADPH, an essential reductant for fatty acid synthesis, thought to drive abnormal fatty acid metabolism and formation of intracellular lipid droplets. In addition to increased shunting to the PPP, it seems likely that impaired glycolysis might also increase flux through the HBP and abnormally elevate O-GlcNAcylation. Thus, determining the exact role of O-GlcNAc regulation in autoimmune T cells could lead to fruitful insight into pathogenic mechanisms driving autoimmune CD4+ T cell inflammation.

Finally, patients with diseases of over-nutrition, such as obesity and type 2 diabetes, have a well-defined chronic, low-grade inflammation. This inflammation has been implicated in much of the downstream pathology associated with increased adiposity, such as atherosclerosis, insulin resistance, and increased risk of autoimmunity and cancer (Ridker et al. 2017; Chehimi et al. 2017). CD4+ T cell effectors, particularly Th1 and Th17 cells, are critical players in the development of atherosclerotic plaques and infiltrate adipose tissue to mediate insulin resistance (Chehimi et al. 2017; Winer et al. 2009). Fatty acid metabolism is abnormally stimulated in memory CD4+ T cells in obese mice and humans, which drives Th17 differentiation (Endo et al. 2015). Additionally, elevated blood glucose, free fatty acid levels, and various metabolites generated from gut dysbiosis create an environment supportive of increased OGlcNAcylation. Thus, O-GlcNAc presents as an intriguing target in ameliorating chronic inflammation in obesity.

Initial studies implicate a bittersweet role for this sugar modification in pro-inflammatory autoimmune diseases, but the specific underlying mechanisms that lead to this enhancement in inflammatory function remain to be clearly elucidated. Future studies are needed to understand how the nutrient-responsive O-GlcNAc modification might play a role in the rapidly expanding field of CD4+ T cell immunometabolism.

Acknowledgements

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK091277 awarded to P. Fields, National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK100595 awarded to C. Slawson, the Molecular Regulation of Cell Development and Differentiation COBRE P30GM122731 awarded to P. Fields and C. Slawson, and a KUMC Biomedical Research Training Program grant awarded to M. Machacek.

References

  1. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham W-R, Muller R, Lochner M, Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20:1327–1333 [DOI] [PubMed] [Google Scholar]
  2. Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B, Pierce R, McClanahan TK, Sadekova S, de Waal Malefyt R (2010) Human Th17 cells comprise heterogeneous subsets including IFN-γ–producing cells with distinct properties from the Th1 lineage. J Immunol 185:679–687 [DOI] [PubMed] [Google Scholar]
  3. Chehimi M, Vidal H, Eljaafari A (2017) Pathogenic role of IL-17-producing immune cells in obesity, and related inflammatory diseases. Journal of Clinical Medicine 6:68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dang EV, Barbi J, Yang H-Y, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen H-R, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146:772–784 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12:295–303 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Endo Y, Asou HK, Matsugae N, Hirahara K, Shinoda K, Tumes DJ, Tokuyama H, Yokote K, Nakayama T (2015) Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep 12:1042–1055 [DOI] [PubMed] [Google Scholar]
  8. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB (2002) The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769–777 [DOI] [PubMed] [Google Scholar]
  9. Geginat J, Paroni M, Facciotti F, Gruarin P, Kastirr I, Caprioli F, Pagani M, Abrignani S (2013) The CD4-centered universe of human T cell subsets. Semin Immunol 25:252–262 [DOI] [PubMed] [Google Scholar]
  10. Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M, Ilkayeva O, Winter PS, Liu X, Priyadharshini B, Slawinska ME, Haeberli L, Huck C, Turka LA, Wood KC, Hale LP, Smith PA, Schneider MA, MacIver NJ, Locasale JW, Newgard CB, Shinohara ML, Rathmell JC (2015) Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest 125:194–207 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gerriets VA, Danzaki K, Kishton RJ, Eisner W, Nichols AG, Saucillo DC, Shinohara ML, MacIver NJ (2016) Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. Eur J Immunol 46:1970–1983 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ghoreschi K, Laurence A, Yang X-P, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun H-W, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic TH17 cells in the absence of TGF-[bgr] signalling. Nature 467:967–971 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Golks A, Tran T-TT, Goetschy JF, Guerini D (2007) Requirement for O-linked N-acetylglucosaminyltransferase in lymphocytes activation. European Molecular Biology Organization 26:4368–4379 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Griffiths M, Keast D (1990) The effect of glutamine on murine splenic leukocyte responses to T and B cell mitogens. Immunol Cell Biol 68:405–408 [DOI] [PubMed] [Google Scholar]
  15. Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, Waschbisch A, Hammer A, Lee D-H, May C, Wilck N, Balogh A, Ostermann AI, Schebb NH, Akkad DA, Grohme DA, Kleinewietfeld M, Kempa S, Thöne J, Demir S, Müller DN, Gold R, Linker RA (2015) Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43:817–829 [DOI] [PubMed] [Google Scholar]
  16. Heikamp EB, Patel CH, Collins S, Waickman A, Oh M-H, Sun I-H, Illei P, Sharma A, Naray-Fejes-Toth A, Fejes-Toth G, Misra-Sen J, Horton MR, Powell JD (2014) The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol 15:457–464 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hewagama A, Gorelik G, Patel D, Liyanarachchi P, Joseph McCune W, Somers E, Gonzalez-Rivera T, The Michigan Lupus C, Strickland F, Richardson B (2013) Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun 41:60–71 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139: 485–498 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jones RG, Thompson CB (2007) Revving the engine: signal transduction fuels T cell activation. Immunity 27:173–178 [DOI] [PubMed] [Google Scholar]
  20. Juang Y-T, Solomou EE, Rellahan B, Tsokos GC (2002) Phosphorylation and O-Linked Glycosylation of Elf-1 Leads to Its Translocation to the Nucleus and Binding to the Promoter of the TCR ζ-Chain. J Immunol 168:2865–2871 [DOI] [PubMed] [Google Scholar]
  21. Kearse KP a GWH (1991) Lymphocyte activation induces rapid changes in nuclear and cytoplasmic glycoproteins. Proc Natl Acad Sci 88: 1701–1705 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496:518–522 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Koga T, Hedrich CM, Mizui M, Yoshida N, Otomo K, Lieberman LA, Rauen T, Crispín JC, Tsokos GC (2014) CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. J Clin Invest 124:2234–2245 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kreppel LK, Hart GW (1999) Regulation of a cytosolic and nuclear O-GlcNAc Transferase: ROLE OF THE TETRATRICOPEPTIDE REPEATS. J Biol Chem 274:32015–32022 [DOI] [PubMed] [Google Scholar]
  25. Lanza C, Tan EP, Zhang Z, Machacek M, Brinker AE, Azuma M, Slawson C (2016) Reduced O-GlcNAcase expression promotes mitotic errors and spindle defects. Cell Cycle 15:1363–1375 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30:92–107 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Liu R, Ma X, Chen L, Yang Y, Zeng Y, Gao J, Jiang W, Zhang F, Li D, Han B, Han R, Qiu R, Huang W, Wang Y, Hao J (2017) MicroRNA-15b suppresses Th17 differentiation and is associated with pathogenesis of multiple sclerosis by targeting O-GlcNAc transferase. J Immunol 198(7):2626–2639 [DOI] [PubMed] [Google Scholar]
  28. Loos J, Roos D (1973) Changes in the carbohydrate metabolism of mitogenically stimulated human peripheral lymphocytes. 3. Stimulation by tuberculin and allogenic cells. Exp Cell Res 79: 136–142 [PubMed] [Google Scholar]
  29. Lund PJ, Elias JE, Davis MM (2016) Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells. J Immunol 197:3086–3098 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Macintyre AN, Gerriets Valerie A., Nichols Amanda G., Michalek Ryan D., Rudolph Michael C., , and Deoliveira Divino, A. SM,Abel E. Dale, Chen Benny J., Hale Laura P., and Rathmell Jeffrey C.. (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20, 61–72 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Martin-Orozco N, Chung Y, Chang SH, Wang Y-H, Dong C (2009) Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 39:216–224 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186:3299–3303 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nakaya M, Xiao Y, Zhou X, Chang J-H, Chang M, Cheng X, Blonska M, Lin X, Sun S-C (2014) Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40:692–705 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nambiar MP, Fisher CU, Warke VG, Krishnan S, Mitchell JP, Delaney N, Tsokos GC (2003) Reconstitution of deficient T cell receptor ζ chain restores T cell signaling and augments T cell receptor/CD3–induced interleukin-2 production in patients with systemic lupus erythematosus. Arthritis Rheum 48:1948–1955 [DOI] [PubMed] [Google Scholar]
  35. Ramakrishnan P, Clark PM, Mason DE, Peters EC, Hsieh-Wilson LC, Baltimore D (2013) Activation of the transcriptional function of the NF-κB protein c-Rel by O-GlcNAc glycosylation. Science Signaling 6:ra75–ra75 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rathmell JC, Elstrom RL, Cinalli RM, Thompson CB (2003) Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur J Immunol 33:2223–2232 [DOI] [PubMed] [Google Scholar]
  37. Reis BS, Lee K, Fanok MH, Mascaraque C, Amoury M, Cohn LB, Rogoz A, Dallner OS, Moraes-Vieira PM, Domingos AI, Mucida D (2015) Leptin receptor signaling in T cells is required for Th17 differentiation. J Immunol 194:5253–5260 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12): 1119–1131 [DOI] [PubMed] [Google Scholar]
  39. Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR (2015) Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab 21:286–297 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Shen Y, Wen Z, Li Y, Matteson EL, Hong J, Goronzy JJ, Weyand CM (2017) Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat Immunol 18:1025–1034 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367–1376 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sinclair LV, Rolf J, Emslie E, Shi Y-B, Taylor PM, Cantrell DA (2013) Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14:500–508 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Slawson C, Zachara NE, Vosseller K, Cheung WD, Lane MD, Hart GW (2005) Perturbations in O-linked β-N-Acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J Biol Chem 280:32944–32956 [DOI] [PubMed] [Google Scholar]
  44. Soroosh P, Wu J, Xue X, Song J, Sutton SW, Sablad M, Yu J, Nelen MI, Liu X, Castro G, Luna R, Crawford S, Banie H, Dandridge RA, Deng X, Bittner A, Kuei C, Tootoonchi M, Rozenkrants N, Herman K, Gao J, Yang XV, Sachen K, Ngo K, Fung-Leung W-P, Nguyen S, de Leon-Tabaldo A, Blevitt J, Zhang Y, Cummings MD, Rao T, Mani NS, Liu C, McKinnon M, Milla ME, Fourie AM, Sun S (2014) Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation. Proc Natl Acad Sci 111:12163–12168 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Swamy M, Pathak S, Grzes KM, Damerow S, Sinclair LV, van Aalten DMF, Cantrell DA (2016) Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat Immunol 17:712–720 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tan EP, Caro S, Potnis A, Lanza C, Slawson C (2013) O-linked N-Acetylglucosamine cycling regulates mitotic spindle organization. J Biol Chem 288:27085–27099 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tsokos GC, Nambiar MP, Juang Y-T (2003) Activation of the Ets transcription factor elf-1 requires phosphorylation and glycosylation. Ann N Y Acad Sci 987:240–245 [DOI] [PubMed] [Google Scholar]
  48. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB, Kaminski J, Xiao S, Horste Z, Gerd M, Pawlak M, Kishi Y, Joller N, Karwacz K, Zhu C, Ordovas-Montanes M, Madi A, Wortman I, Miyazaki T, Sobel RA, Park H, Regev A, Kuchroo VK (2015) CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163:1413–1427 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Winer S, Paltser G, Chan Y, Tsui H, Engleman E, Winer D, Dosch HM (2009) Obesity predisposes to Th17 bias. Eur J Immunol 39:2629–2635 [DOI] [PubMed] [Google Scholar]
  51. Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496:513–517 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484 [DOI] [PubMed] [Google Scholar]
  53. Yan Y, Zhang G-X, Gran B, Fallarino F, Yu S, Li H, Cullimore ML, Rostami A, Xu H (2010) IDO Upregulates regulatory T cells via tryptophan Catabolite and suppresses Encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185:5953–5961 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yu X, Rollins D, Ruhn KA, Stubblefield JJ, Green CB, Kashiwada M, Rothman PB, Takahashi JS, Hooper LV (2013) TH17 cell differentiation is regulated by the circadian clock. Science 342:727–730 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Zhang MA, Rego D, Moshkova M, Kebir H, Chruscinski A, Nguyen H, Akkermann R, Stanczyk FZ, Prat A, Steinman L, Dunn SE (2012) Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way. Proc Natl Acad Sci 109:9505–9510 [DOI] [PMC free article] [PubMed] [Google Scholar]

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