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Vitamin C and immune cell function in inflammation and cancer

Abel Ang, Juliet M. Pullar, Margaret J. Currie and 1 more

Biochemical Society Transactions · 2018 · Review · CC BY

doi:10.1042/bst20180169

Abstract

Vitamin C (ascorbate) is maintained at high levels in most immune cells and can affect many aspects of the immune response. Intracellular levels generally respond to variations in plasma ascorbate availability, and a combination of inadequate intake and increased turnover during severe stress can result in low plasma ascorbate status. Intracellular ascorbate supports essential functions and, in particular, acts as an enzyme cofactor for Fe- or Cu-containing oxygenases. Newly discovered enzymes in this family regulate cell metabolism and epigenetics, and dysregulation of their activity can affect cell phenotype, growth and survival pathways, and stem cell phenotype. This brief overview details some of the recent advances in our understanding of how ascorbate availability can affect the hydroxylases controlling the hypoxic response and the DNA and histone demethylases. These processes play important roles in the regulation of the immune system, altering cell survival pathways, metabolism and functions.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

Humans have an absolute requirement for vitamin C (ascorbate) as part of their diet, and deficiency due to inadequate intake is associated with a plethora of symptoms, reflecting the diverse functions attributed to the vitamin. There is widespread belief that ascorbate supports the immune system, and claims along this line are frequently encountered, including on commercially available dietary supplements. Since its discovery more than 80 years ago, the function of ascorbate in the immune system has been the subject of much research and more than a little controversy. One of the main drivers of this interest is that leukocytes accumulate the vitamin to high intracellular concentrations, signalling an important role for it in these cells.

Additionally, in the last 15 years, the many cofactor functions of ascorbate have come to the fore. It is well established that ascorbate is a specific cofactor for many biosynthetic enzymes including dopamine β-hydroxylase, which converts dopamine to norepinephrine, and the collagen prolyl and lysyl hydroxylases which form cross-links to stabilise the tertiary structure of collagen. More recently, however, it has become apparent that ascorbate is also a cofactor for newly characterised hydroxylases that regulate gene transcription and cell signalling pathways. These hydroxylases belong to the family of Fe-containing 2-oxoglutarate-dependent dioxygenases; members of this family are widespread throughout biology, and include enzymes involved in biosynthesis, post-translational protein modification and the oxidative demethylation of methylcytosine and methylated histone residues. Examples of these enzymes include N-trimethyllysine hydroxylase and γ-butyrobetaine dioxygenase that synthesise carnitine, and the prolyl, lysyl and arginine hydroxylases that modify collagen and the alpha regulatory subunit of the hypoxia-inducible factors.

This short review will focus on the cell signalling and gene regulatory (cofactor) actions of vitamin C and their potential roles in regulating the immune system. The contributions of ascorbate as an antioxidant in immune cells have been well reviewed by others and will not be discussed here. We will consider the functional effects of ascorbate on cells of both the innate and adaptive immune responses that particularly reflect the cofactor activity of ascorbate and include a discussion of the role of vitamin C on immune cells in cancer.

Ascorbate levels in immune cells

The optimal concentration of ascorbate required for its cofactor activity supporting the Fe- and Cu-containing enzymes in vitro is in the mM range, similar to the intracellular levels measured in many cell types. The ascorbate content of immune cells is also in this range and reflects plasma availability. Intracellular ascorbate concentrations in circulating lymphocytes, monocytes and neutrophils have been reported to be ∼3.5, ∼3 and ∼1.5 mM, respectively, when plasma levels are at least 50 µM, reflecting the status in healthy individuals consuming ≥100 mg ascorbate daily. However, when plasma levels fall below 50 µM, immune cell ascorbate content decreases, with intracellular concentrations at ∼1.5, 1.2 and 0.5 mM in lymphocytes, monocytes and neutrophils, respectively, when plasma levels are ≤20 µM. Plasma levels below 23 µM represent a state of hypovitaminosis C and are commonly seen in individuals with low fresh fruit and vegetable intake. In addition, there is substantial evidence that plasma and cellular ascorbate levels are depressed in conditions of active inflammation and in cancer patients, including patients with haematological cancers. Severely depleted plasma levels of ≤20 µM are commonly reported, particularly in very ill patient populations. Ascorbate loss during illness is thought to reflect increased turnover due to oxidative and metabolic stress. This variable availability of ascorbate may modulate ascorbate-dependent enzyme reactions and thereby affect immune cell function.

The cellular ascorbate content referred to above applies to mature circulating white blood cells. A recent report indicated that haematopoietic and multipotent stem cells and haematopoietic progenitor cells in the bone marrow contain 2- to 20-fold more ascorbate than differentiated cells and that increased ascorbate content correlated with increased expression of the specific ascorbate transporter, SVCT2. This information suggests an essential role for ascorbate in bone marrow stem cell differentiation. Evidence for this is accumulating, with recent reports of ascorbate-mediated regulation of epigenetic programming and differentiation in bone marrow stem cells and particularly in myeloid leukaemia cells containing mutations in TET2 or IDH1. For more in-depth information, the reader is referred to recent reviews of this interesting and fast-developing field of research.

The role of ascorbate in the hypoxic response and implications for immune cell function

The hydroxylase enzymes that regulate the activity of the hypoxia-inducible factors (HIF)s require ascorbate for optimal activity. The HIFs are controlled by hydroxylation of proline and asparagine residues on the regulatory alpha subunit and, in response to changes in oxygen availability, they direct the transcription of hundreds of genes via the hypoxia response element. The dependence of the hydroxylases on ascorbate as a cofactor has been demonstrated in cell-free systems, with other reducing agents such as glutathione being very much less effective as a recycler of the hydroxylase active site Fe2+. Depleted intracellular ascorbate levels have been shown to contribute to the up-regulation of HIF activation, particularly under conditions of mild or moderate hypoxia.

The interaction between ascorbate and the HIFs is relevant to the function of immune cells in both inflammation and cancer. Inflammatory sites are known to be under hypoxic stress, potentially as a consequence of the increased oxidative metabolism of inflammatory cells. Growing tumours are also well characterised as being hypoxic tissues due to rapid proliferation and outgrowth of the established blood supply. The resulting up-regulation of the HIFs is instrumental in the activation of glycolysis, angiogenesis, resistance to chemotherapy and the promotion of a stem cell phenotype, thereby promoting tumour growth and metastasis. At inflammatory sites and in tumour tissue, the hypoxic environment affects immune cell function and, given the interdependence between the activation of the HIFs and cellular ascorbate, we propose that many effects of ascorbate on immune cell function are likely to reflect the regulation of HIF-mediated functions. Figure 1 shows a summary of the interactions that are discussed in the sections below.

Effects of HIFs and ascorbate on immune cells

Immune cells undergo dramatic metabolic changes following activation, and increased aerobic glycolytic activity and fatty acid oxidation have been observed. These metabolic changes, once thought to be a consequence of cell activation, are now being re-examined as a mechanism for phenotype switching, termed metabolic reprogramming (reviewed in ref.). Central to this switch are the HIF proteins which not only up-regulate the glycolytic machinery but also direct the inflammatory and immune response (reviewed in ref.).

Monocytes/macrophages

The high ascorbate concentrations in monocytes may be related to their dependency on HIF for many essential functions. HIF-1 has been shown to be activated in monocytes following activation with phorbol esters and pathogenic stimuli, even under non-hypoxic conditions. That HIF activation is an integral part of monocyte function is indicated by the demonstrations that HIF-1α or HIF-2α deletion in myeloid cells caused profound impairment of cell aggregation, motility, invasiveness and bacterial killing, resulting in decreased bacterial resistance and failure to restrict systemic spread of a localised infection. HIF-1/2 appears to be important for monocyte-mediated host defence; HIF-1 activation has been shown to contribute to disease progression in colitis and myeloid HIF-1α knockout shifts the balance to an anti-inflammatory phenotype resulting in a less severe inflammation. The sepsis-related host immunosuppressive monocyte phenotype has also been shown to be mediated by chronic HIF-1α expression, resulting in supressed pro-inflammatory cytokine expression and increased ability to induce Treg cell polarisation.

In cancer, activation of HIF-1/2 in monocytes has been implicated in the development and phenotype of tumour-associated macrophages. This is associated with an increased M2-like gene profile, increased expression of immunosuppressive and pro-tumour proteins such as arginase 1, iNOS and VEGF, as well as induction of PD-L1 expression. These changes lead to greater monocyte/macrophage tumour invasion and tumour cytotoxic T-cell suppression. Interestingly, a macrophage-targeted HIF-1α and HIF-2α knockout resulted in delayed tumour progression in models of breast tumour, fibrosarcoma and colitis-associated colon carcinoma.

The potential complexity of ascorbate engagement with immune cells in the tumour microenvironment is well demonstrated by the observations that dendritic cells treated with ascorbate secreted increased levels of IL-12p70 after activation with LPS and induced more Th1 cytokine and IFN-γ, but less Th2-cytokine, IL-5 expression in naive T cells. Ascorbate-treated dendritic cells also increased the frequency of IFN-γ + T cells when co-cultured with both CD4+ and CD8+ T cells and demonstrated an improved anti-tumour effect.

Neutrophils

Neutrophils are short-lived cells that are the first responders to an inflammatory challenge. Their recruitment to, and clearance from, inflammatory sites is dependent on the regulation of cell death and survival pathways. It appears that HIF-1 and ascorbate are intimately involved in determining neutrophil cell fate. Hypoxia has been shown to prolong neutrophil survival via activation of HIF-1 and its downstream pathways. HIF-1 activation also enhanced overall neutrophil antibacterial function as demonstrated by increased susceptibility to bacterial keratitis in mice when HIF-1 was inhibited. This was supported by findings of delayed rates of apoptosis and enhanced bacterial phagocytosis under normoxic conditions in neutrophils from patients with a monoallelic mutation of von Hippel Lindau protein who exhibit a ‘partial hypoxic’ phenotype. These results suggest that a functional hypoxic response supports neutrophil function at hypoxic inflammatory sites in vivo. A similar anti-apoptotic phenotype in ascorbate-deficient neutrophils was shown to be associated with HIF-1 activation under normoxic conditions. Recognition of aged neutrophils by macrophages was also reported and neutrophil clearance from an inflammatory site was delayed in deficient cells. Interestingly, increasing neutrophil ascorbate content was found to inhibit neutrophil Fas-induced cell death as well as the rates of neutrophil and monocyte apoptosis in patients with sepsis. Also, in the ascorbate-dependent Gulo−/− mouse, a high ascorbate diet was found to increase circulating granulocyte and monocyte numbers.

Not all effects of ascorbate on neutrophil function will be HIF-related. Severe ascorbate deficiency has been shown to impair neutrophil bactericidal ability towards phagocytosed pathogens following infection with actimoycetes and K pneumoniae, possibly as a result of altered oxidative capacity. Neutrophils from individuals with suboptimal circulating ascorbate levels showed a modest increase in neutrophil chemotaxis and oxidative burst ex vivo following supplementation to restore vitamin C status to healthy levels. Vitamin C deficiency also increased the generation of neutrophil extracellular traps (NETs) in the Gulo−/− mouse.

T cells

Differentiation of CD4 T cells dictates the type of inflammatory response occurring via the development of different T-helpers and iTreg subsets and their corresponding effector function. Therefore, depending on the nature of the insult or source of inflammation, the prevailing ratio and species of T cells could alter the outcome. HIF-1 appears to play an important, although unresolved, role in T-cell differentiation. For example, HIF-1α T-cell-targeted knockout protected mice from autoimmune neuro-inflammation and was associated with a shift from TH17 to Treg response, possibly by increasing glycolysis, while the opposite was observed in irritable bowel disease where T-cell HIF-1α knockout increased TH1 and TH17 leading to severe colonic inflammation. HIF-1α-mediated myeloid- and dendritic cell-driven differentiation of T cells also greatly affected the inflammatory outcome; HIF-1α knockout in myeloid cells resulted in lesser TH17 prevalence and decreased inflammation. In dendritic cells, HIF-1 knockout resulted in impaired Treg development and increased inflammation, and HIF-1-mediated events were reported to limit Th1 cell development by preventing IL-12 production and to exacerbate Leishmania infections.

Apart from T-cell differentiation, HIF-1 has also been shown to affect T-cell activation and function. HIF activation enhanced the expression of effector molecules, co-stimulatory receptors, activation and inhibitory receptors, and key transcriptional regulators of effector and memory cell differentiation. However, this was in contrast with a previous report showing higher levels of pro-inflammatory cytokines, stronger antibacterial effects and much better survival of septic mice with T-cell targeted deletion of HIF-1α.

In cancer, HIF-1 activation is associated with expression of CD69 (a marker of activated T cells) on cytotoxic T lymphocytes (CTLs) in hypoxic regions of tumour, suggesting a pro-tumour killing role for HIF-1α. This is supported by two studies, showing that T-cell HIF-1 activation significantly delayed tumour growth and, conversely, accelerated tumour progression in the presence of HIF-1α knockout CTLs in a murine model of ectopic B16 melanoma.

There have been many studies that have suggested that ascorbate influences lymphocyte differentiation, including early studies that indicated that increased circulating lymphocytes were associated with ascorbate availability. High ascorbate supplementation for one-year also significantly increased all circulating leukocytes, including lymphocytes, in the SMP30KO ascorbate-dependent mice. Ascorbate was required for the progression of mouse bone marrow-derived progenitor cells into functional T-lymphocytes and also increased the NK cell population in vitro. Many of these effects show a significant correlation with the regulation of the TET and Jumonji demethylases and epigenetic changes, rather than with the expression of HIF-1. This topic is discussed in the following section.

Ascorbate and the regulation of epigenetics in immune cells

In mammals, one of the most widespread epigenetic modifications is DNA cytosine methylation which can be actively reversed by the TET enzymes that catalyse the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Ascorbate availability enhances TET activity through its cofactor function, likely maintaining the active site Fe2+ of these dioxygenases. Although other reducing agents could reduce Fe3+ and promote TET activity in a cell free system, ascorbate was shown to be the most efficient and glutathione was incapable of increasing murine embryonic TET activity compared with equimolar ascorbate. The Jumonji C domain-containing histone demethylases (JHDMs) are also members of the Fe- and 2-oxoglutarate-dependent dioxygenase family and similarly to TETs, full enzyme activity of JHDMs occurs in the presence of ascorbate. The JHDMs are the third and largest class of demethylase enzymes, capable of removing all three histone lysine-methylation states through oxidative reactions.

Monoytes/macrophages

Epigenetic regulation plays an important role in macrophage differentiation, with rapid TET-dependent demethylation observed in colony-stimulating factor-1-differentiated human monocytes. TET2 transcription was further induced by LPS but not by IL-4 stimulation. The genes affected by TET-mediated demethylation are part of ten consolidated pathways related to the regulation of actin cytoskeleton, phagocytosis and the innate immune system, and in macrophages, TET2 is thought to restrain the inflammatory response by up-regulating expression of genes involved in dampening Toll-like receptor 4 signalling. This notion is supported by a report showing TET2 represses IL-6 production during LPS-induced inflammation and that TET2 knockout exacerbates the expression of macrophage pro-inflammatory molecules such as IL-6, MCP-1 and MCP-3 in response to LPS stimulation, resulting in an enhanced inflammatory response.

The JHDM enzyme JMJD3 is expressed in monocytes/macrophages and is inducible by differentiating factors as well as by pathogenic and damage-associated molecules. Although JMJD3 has been shown to affect gene expression in macrophages, the role of JMJD3 in macrophage function is still unclear. For example, 70% of macrophage–LPS–inducible genes were found to be JMJD3 targets but only a few hundred genes, including inducible inflammatory genes, were moderately affected by JMJD3 deletion. However, Kruidenier et al. demonstrated a drastic drop in LPS-induced cytokine expression using a specific JMJD3 inhibitor and siRNA, among them TNF-α. In contrast, Satoh et al. showed no effect on M1 cytokine secretion following LPS stimulation in JMJD3 knockout macrophages including TNF-α. Contradictions aside, two studies looking at macrophage response to parasitic infection have associated JMJD3 demethylation activity with acquisition of an M2 phenotype, demonstrated by up-regulation of M2 proteins such as Arg1, Ym1, Fizz1, MR and iNOS. Two other studies have associated JMJD3 activity with an M1 macrophage phenotype following serum amyloid A stimulation and in arthritis resulting in induction of pro-inflammatory cytokines.

Epigenetic processes regulated by the demethylases are associated with leukaemogenesis and ascorbate availability has been closely linked to this phenomenon. As mentioned above, haematopoietic stem and progenitor cells (HSPCs) accumulate high intracellular concentrations of ascorbate, and this is essential for HSPC differentiation via support of TET2 activity. TET2 inhibition in HSPCs by ascorbate depletion retards differentiation and increases HPSC frequency. TET2 mutations are also known to co-operate with FLT3ITD mutations to cause acute myeloid leukaemia. Ascorbate depletion coupled with FLT3ITD mutations was adequate for leukaemogenesis. It appears then, that ascorbate accumulation within HSCs promotes TET function in vivo, limiting HSPC frequency and suppressing leukaemogenesis. These findings were corroborated in part by another group that described the use of ascorbate as a combination therapy for treating leukaemia. Patients with leukaemia often have low plasma ascorbate levels and the capacity for ascorbate to influence the epigenetic drivers of some leukaemias has led to conjecture that increased ascorbate supply may provide clinical benefit to some individuals with leukaemia. Two recent publications have provided support for this hypothesis.

Dendritic cells

DNA demethylation changes occur during the development of monocytes into immature DCs and mature DCs. TET2 represses late-phase expression of dendritic cell pro-inflammatory molecules such as IL-6, MCP-1 and MCP-3 in response to LPS stimulation and TET2 knockout results in a greater degree of inflammatory response in mice challenged with LPS and colitis. KDM5B acts to repress type I IFN and other innate cytokines in DCs to promote an altered immune response following RSV infection that contributes to the development of chronic disease.

T cells

Widespread DNA methylation remodelling has been reported at genes and cell-specific enhancers with known T-cell function during human CD4+ T differentiation, and TET2 was reported to be the critical DNA demethylase involved in the differentiation of TH1 and TH17 cells, leading to activation of effector cytokine gene expression. TET2 has also been shown to regulate CD8+ T-cell fate, particularly in formation of memory CD8+ T cells. Prolonged antigen stimulation in peptide immunotherapy is associated with demethylation of conserved regions of PD-1 promoter, possibly via TET, leading to sustained PD-1 expression in CD4+ effector T cells.

Profound demethylation of histone H3K27 is observed after activation in CD4+ T cells and corresponds to pathways crucial to T-cell function, including T-cell activation and the regulation of the JAK/STAT pathways. Deletion of the histone demethylase JMJD3 was found to regulate gene expression resulting in TH2 and TH17 differentiation and inhibiting TH1 and Treg cell differentiation via altered methylation status of H3K27 and/or H3K4.

Recent studies focusing on the role of ascorbate in T-cell differentiation and function suggest close alignment with epigenetic regulation and demethylase activity. Initial work showed ascorbate to be required for the progression of mouse bone marrow-derived progenitor cells into functional T-lymphocytes in vitro and in vivo by a JMJC-mediated process. Subsequent studies reported ascorbate-mediated stabilisation of Foxp3 expression in TGF-β-induced Tregs by TET enzymes. Also, ascorbate enhanced alloantigen-induced Treg suppressive capacity in skin allograft and GVHD in mice was attributed to the stabilisation of Foxp3 expression, presumably via demethylation of Foxp3 and other Treg-specific epigenetic genes. Apart from Tregs, ascorbate has also been implicated in the maintenance of TH17 phenotype by increasing IL-17 expression in TH17-differentiated T cells via reduced trimethylation of histone H3 lysine 9 (H3K9me3) in the regulatory elements of the IL-17 locus.

NK cells

Many recent studies have demonstrated the impact of TET- and JHDM-mediated demethylation on NKT cell development, proliferation and function. Interestingly, inhibition of the H3K27 demethylase reduced IFN-γ, TNF-α, GM-CSF and IL-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells.

Summary

The demonstrated dependency of the Fe-containing 2-oxoglutarate-dependent dioxygenase family on ascorbate availability and the involvement of members of this family of enzymes on many immune cell functions provide a rational basis for the belief that ascorbate supports the immune system. Ascorbate availability will influence HIF activation and immune cell function in hypoxic inflammatory and tumour environments, affecting the resolution of inflammation and potentially tumour survival in as yet unknown ways. There is also an impressive amount of information emerging that highlights the impact of the TET DNA demethylases and some histone demethylases on epigenetic remodelling of immune cells. These enzymes have also been shown to be highly responsive to ascorbate, and new insights into ascorbate function in immunity will no doubt continue to emerge.

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    Bonham M.J., Abu-Zidan F.M., Simovic M.O., Sluis K.B., Wilkinson A., Winterbourn C.C. et al. (1999 ) Early ascorbic acid depletion is related to the severity of acute pancreatitis. Br. J. Surg. 86, 1296–1301

    Not in our library10.1046/j.1365-2168.1999.01182.x

  38. 38.

    Jiang Q., Lykkesfeldt J., Shigenaga M.K., Shigeno E.T., Christen S. and Ames B.N. (2002 ) γ-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation. Free Radic. Biol. Med. 33, 1534–1542

    Not in our library10.1016/s0891-5849(02)01091-2

  39. 39.

    Bakaev V.V. and Duntau A.P. (2004 ) Ascorbic acid in blood serum of patients with pulmonary tuberculosis and pneumonia. Int. J. Tuber. Lung Dis. 8, 263–266 PMID:

    Not in our library

  40. 40.
    Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes · 2017
    No notice
  41. 41.

    Basu T.K., Raven R.W., Dickerson J.W. and Williams D.C. (1974 ) Leucocyte ascorbic acid and urinary hydroxyproline levels in patients bearing breast cancer with skeletal metastases. Eur. J. Cancer 10, 507–511

    Not in our library10.1016/0014-2964(74)90074-7

  42. 42.

    Anthony H.M. and Schorah C.J. (1982 ) Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte-related host resistance. Br. J. Cancer 46, 354–367

    Not in our library10.1038/bjc.1982.211

  43. 43.

    Mayland C.R., Bennett M.I. and Allan K. (2005 ) Vitamin C deficiency in cancer patients. Palliat. Med. 19, 17–20

    Not in our library10.1191/0269216305pm970oa

  44. 44.

    Huijskens M.J., Wodzig W.K., Walczak M., Germeraad W.T. and Bos G.M. (2016 ) Ascorbic acid serum levels are reduced in patients with hematological malignancies. Results Immunol. 6, 8–10

    Not in our library10.1016/j.rinim.2016.01.001

  45. 45.

    Abou-Seif M.A., Rabia A. and Nasr M. (2000 ) Antioxidant status, erythrocyte membrane lipid peroxidation and osmotic fragility in malignant lymphoma patients. Clin. Chem. Lab. Med. 38, 737–742

    Not in our library10.1515/cclm.2000.104

  46. 46.

    Blair C.K., Roesler M., Xie Y., Gamis A.S., Olshan A.F., Heerema N.A. et al. (2008 ) Vitamin supplement use among children with Down's syndrome and risk of leukaemia: a Children's Oncology Group (COG) study. Paediatr. Perinat. Epidemiol. 22, 288–295

    Not in our library10.1111/j.1365-3016.2008.00928.x

  47. 47.

    Kennedy D.D., Tucker K.L., Ladas E.D., Rheingold S.R., Blumberg J. and Kelly K.M. (2004 ) Low antioxidant vitamin intakes are associated with increases in adverse effects of chemotherapy in children with acute lymphoblastic leukemia. Am. J. Clin. Nutr. 79, 1029–1036

    Not in our library10.1093/ajcn/79.6.1029

  48. 48.

    Nakagawa K. (2000 ) Effect of chemotherapy on ascorbate and ascorbyl radical in cerebrospinal fluid and serum of acute lymphoblastic leukemia. Cell. Mol. Biol. 46, 1375–1381 PMID:

    Not in our library

  49. 49.

    Neyestani T.R., Fereydouni Z., Hejazi S., Salehi-Nasab F., Nateghifard F., Maddah M. et al. (2007 ) Vitamin C status in Iranian children with acute lymphoblastic leukemia: evidence for increased utilization. J. Pediatr. Gastroenterol. Nutr. 45, 141–144

    Not in our library10.1097/mpg.0b013e31804c5047

  50. 50.

    Sharma A., Tripathi M., Satyam A. and Kumar L. (2009 ) Study of antioxidant levels in patients with multiple myeloma. Leuk. Lymphoma 50, 809–815

    Not in our library10.1080/10428190902802323

  51. 51.

    Evans-Olders R., Eintracht S. and Hoffer L.J. (2010 ) Metabolic origin of hypovitaminosis C in acutely hospitalized patients. Nutrition 26, 1070–1074

    Not in our library10.1016/j.nut.2009.08.015

  52. 52.

    Gan R., Eintracht S. and Hoffer L.J. (2008 ) Vitamin C deficiency in a university teaching hospital. J. Am. Coll. Nutr. 27, 428–433

    Not in our library10.1080/07315724.2008.10719721

  53. 53.

    Agathocleous M., Meacham C.E., Burgess R.J., Piskounova E., Zhao Z., Crane G.M. et al. (2017 ) Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476–481

    Not in our library10.1038/nature23876

  54. 54.

    Mastrangelo D., Pelosi E., Castelli G., Lo-Coco F. and Testa U. (2018 ) Mechanisms of anti-cancer effects of ascorbate: cytotoxic activity and epigenetic modulation. Blood Cells Mol. Dis. 69, 57–64

    Not in our library10.1016/j.bcmd.2017.09.005

  55. 55.

    Mingay M., Chaturvedi A., Bilenky M., Cao Q., Jackson L., Hui T. et al. (2018 ) Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia. Leukemia 32, 11–20

    Not in our library10.1038/leu.2017.171

  56. 56.

    Gillberg L., Orskov A.D., Liu M., Harslof L.B.S., Jones P.A. and Gronbaek K. (2018 ) Vitamin C—a new player in regulation of the cancer epigenome. Semin. Cancer Biol. 51, 59–67

    Not in our library10.1016/j.semcancer.2017.11.001

  57. 57.
    Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence · 2018
    No notice
  58. 58.

    Kaelin W.G.J. and Ratcliffe P.J. (2008 ) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402

    Not in our library10.1016/j.molcel.2008.04.009

  59. 59.

    Ratcliffe P.J. (2013 ) Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J. Physiol. 591(Pt 8), 2027–2042

    Not in our library10.1113/jphysiol.2013.251470

  60. 60.

    Semenza G.L. (2010 ) HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56

    Not in our library10.1016/j.gde.2009.10.009

  61. 61.

    Ozer A. and Bruick R.K. (2007 ) Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one? Nat. Chem. Biol. 3, 144–153

    Not in our library10.1038/nchembio863

  62. 62.

    Jaakkola P., Mole D.R., Tian Y.M., Wilson M.I., Gielbert J., Gaskell S.J. et al. (2001 ) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472

    Not in our library10.1126/science.1059796

  63. 63.

    Hirsila M., Koivunen P., Gunzler V., Kivirikko K.I. and Myllyharju J. (2003 ) Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 278, 30772–30780

    Not in our library10.1074/jbc.m304982200

  64. 64.

    Nytko K.J., Maeda N., Schlafli P., Spielmann P., Wenger R.H. and Stiehl D.P. (2011 ) Vitamin C is dispensable for oxygen sensing in vivo. Blood 117, 5485–5493

    Not in our library10.1182/blood-2010-09-307637

  65. 65.

    Nytko K.J., Spielmann P., Camenisch G., Wenger R.H. and Stiehl D.P. (2007 ) Regulated function of the prolyl-4-hydroxylase domain (PHD) oxygen sensor proteins. Antioxid. Redox Signal. 9, 1329–1338

    Not in our library10.1089/ars.2007.1683

  66. 66.

    Campbell E.J., Vissers M.C. and Dachs G.U. (2016 ) Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo−/− mice. Hypoxia 4, 41–52

    Not in our library10.2147/hp.s103088

  67. 67.

    Colgan S.P., Campbell E.L. and Kominsky D.J. (2016 ) Hypoxia and mucosal inflammation. Annu. Rev. Pathol. 11, 77–100

    Not in our library10.1146/annurev-pathol-012615-044231

  68. 68.

    Whyte M.K. and Walmsley S.R. (2014 ) The regulation of pulmonary inflammation by the hypoxia-inducible factor-hydroxylase oxygen-sensing pathway. Ann. Am. Thorac. Soc. 11, S271–S276

    Not in our library10.1513/annalsats.201403-108aw

  69. 69.

    Campbell E.L., Bruyninckx W.J., Kelly C.J., Glover L.E., McNamee E.N., Bowers B.E. et al. (2014 ) Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40, 66–77

    Not in our library10.1016/j.immuni.2013.11.020

  70. 70.

    Adam J., Yang M., Soga T. and Pollard P.J. (2014 ) Rare insights into cancer biology. Oncogene 33, 2547–2556

    Not in our library10.1038/onc.2013.222

  71. 71.

    Brahimi-Horn M.C., Chiche J. and Pouysségur J. (2007 ) Hypoxia and cancer. J. Mol. Med. 85, 1301–1307

    Not in our library10.1007/s00109-007-0281-3

  72. 72.

    Potter C. and Harris A.L. (2004 ) Hypoxia inducible carbonic anhydrase IX, marker of tumour: hypoxia, survival pathway and therapy target. Cell Cycle 3, 159–162

    Not in our library10.4161/cc.3.2.618

  73. 73.

    Semenza G.L. (2015 ) Regulation of the breast cancer stem cell phenotype by hypoxia-inducible factors. Clin. Sci. 129, 1037–1045

    Not in our library10.1042/cs20150451

  74. 74.

    Karaczyn A., Ivanov S., Reynolds M., Zhitkovich A., Kasprzak K.S. and Salnikow K. (2006 ) Ascorbate depletion mediates up-regulation of hypoxia-associated proteins by cell density and nickel. J. Cell. Biochem. 97, 1025–1035

    Not in our library10.1002/jcb.20705

  75. 75.

    Knowles H.J., Mole D.R., Ratcliffe P.J. and Harris A.L. (2006 ) Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1. Cancer Res. 66, 2600–2607

    Not in our library10.1158/0008-5472.can-05-2351

  76. 76.

    Knowles H.J., Raval R.R., Harris A.L. and Ratcliffe P.J. (2003 ) Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res. 63, 1764–1768 PMID:

    Not in our library

  77. 77.

    Kuiper C., Dachs G.U., Munn D., Currie M.J., Robinson B.A., Pearson J.F. et al. (2014 ) Increased tumor ascorbate is associated with extended disease-free survival and decreased hypoxia-inducible factor-1 activation in human colorectal cancer. Front. Oncol. 4, 10

    Not in our library10.3389/fonc.2014.00010

  78. 78.

    Kuiper C., Molenaar I.G., Dachs G.U., Currie M.J., Sykes P.H. and Vissers M.C. (2010 ) Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res. 70, 5749–5758

    Not in our library10.1158/0008-5472.can-10-0263

  79. 79.

    Pearce E.L. and Pearce E.J. (2013 ) Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643

    Not in our library10.1016/j.immuni.2013.04.005

  80. 80.

    Corcoran S.E. and O'Neill L.A. (2016 ) HIF1α and metabolic reprogramming in inflammation. J. Clin. Invest. 126, 3699–3707

    Not in our library10.1172/jci84431

  81. 81.

    Palsson-McDermott E.M. and O'Neill L.A. (2013 ) The Warburg effect then and now: from cancer to inflammatory diseases. BioEssays 35, 965–973

    Not in our library10.1002/bies.201300084

  82. 82.

    Oda T., Hirota K., Nishi K., Takabuchi S., Oda S., Yamada H. et al. (2006 ) Activation of hypoxia-inducible factor 1 during macrophage differentiation. Am. J. Physiol. Cell Physiol. 291, C104–C113

    Not in our library10.1152/ajpcell.00614.2005

  83. 83.

    Li C., Wang Y., Li Y., Yu Q., Jin X., Wang X. et al. (2018 ) HIF1α-dependent glycolysis promotes macrophage functional activities in protecting against bacterial and fungal infection. Sci. Rep. 8, 3603

    Not in our library10.1038/s41598-018-22039-9

  84. 84.

    Cramer T., Yamanishi Y., Clausen B.E., Forster I., Pawlinski R., Mackman N. et al. (2003 ) HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657

    Not in our library10.1016/s0092-8674(03)00154-5

  85. 85.

    Peyssonnaux C., Datta V., Cramer T., Doedens A., Theodorakis E.A., Gallo R.L. et al. (2005 ) HIF-1α expression regulates the bactericidal capacity of phagocytes. J. Clin. Invest. 115, 1806–1815

    Not in our library10.1172/jci23865

  86. 86.

    Braverman J., Sogi K.M., Benjamin D., Nomura D.K. and Stanley S.A. (2016 ) HIF-1α is an essential mediator of IFN-γ-dependent immunity to Mycobacterium tuberculosis. J. Immunol. 197, 1287–1297

    Not in our library10.4049/jimmunol.1600266

  87. 87.

    Imtiyaz H.Z., Williams E.P., Hickey M.M., Patel S.A., Durham A.C., Yuan L.J. et al. (2010 ) Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714

    Not in our library10.1172/jci39506

  88. 88.
    Knockdown of myeloid cell hypoxia-inducible factor-1α ameliorates the acute pathology in DSS-induced colitis. · 2017
    Not checked
  89. 89.

    Shalova I.N., Lim J.Y., Chittezhath M., Zinkernagel A.S., Beasley F., Hernandez-Jimenez E. et al. (2015 ) Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α. Immunity 42, 484–498

    Not in our library10.1016/j.immuni.2015.02.001

  90. 90.

    Colegio O.R., Chu N.Q., Szabo A.L., Chu T., Rhebergen A.M., Jairam V. et al. (2014 ) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563

    Not in our library10.1038/nature13490

  91. 91.

    Corzo C.A., Condamine T., Lu L., Cotter M.J., Youn J.I., Cheng P. et al. (2010 ) HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453

    Not in our library10.1084/jem.20100587

  92. 92.

    Noman M.Z., Desantis G., Janji B., Hasmim M., Karray S., Dessen P. et al. (2014 ) PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790

    Not in our library10.1084/jem.20131916

  93. 93.

    Doedens A.L., Stockmann C., Rubinstein M.P., Liao D., Zhang N., DeNardo D.G. et al. (2010 ) Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res. 70, 7465–7475

    Not in our library10.1158/0008-5472.can-10-1439

  94. 94.

    Henke N., Ferreiros N., Geisslinger G., Ding M.G., Essler S., Fuhrmann D.C. et al. (2016 ) Loss of HIF-1α in macrophages attenuates AhR/ARNT-mediated tumorigenesis in a PAH-driven tumor model. Oncotarget 7, 25915–25929

    Not in our library10.18632/oncotarget.8297

  95. 95.

    Jeong Y.J., Hong S.W., Kim J.H., Jin D.H., Kang J.S., Lee W.J. et al. (2011 ) Vitamin C-treated murine bone marrow-derived dendritic cells preferentially drive naïve T cells into Th1 cells by increased IL-12 secretions. Cell. Immunol. 266, 192–199

    Not in our library10.1016/j.cellimm.2010.10.005

  96. 96.

    Jeong Y.J., Kim J.H., Hong J.M., Kang J.S., Kim H.R., Lee W.J. et al. (2014 ) Vitamin C treatment of mouse bone marrow-derived dendritic cells enhanced CD8+ memory T cell production capacity of these cells in vivo. Immunobiology 219, 554–564

    Not in our library10.1016/j.imbio.2014.03.006

  97. 97.

    Maianski N.A., Maianski A.N., Kuijpers T.W. and Roos D. (2004 ) Apoptosis of neutrophils. Acta Haematol. 111, 56–66

    Not in our library10.1159/000074486

  98. 98.

    Mecklenburgh K.I., Walmsley S.R., Cowburn A.S., Wiesener M., Reed B.J., Upton P.D. et al. (2002 ) Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis. Blood 100, 3008–3016

    Not in our library10.1182/blood-2002-02-0454

  99. 99.

    Walmsley S.R., Cowburn A.S., Clatworthy M.R., Morrell N.W., Roper E.C., Singleton V. et al. (2006 ) Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis. Blood 108, 3176–3178

    Not in our library10.1182/blood-2006-04-018796

  100. 100.

    Walmsley S.R., Print C., Farahi N., Peyssonnaux C., Johnson R.S., Cramer T. et al. (2005 ) Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. J. Exp. Med. 201, 105–115

    Not in our library10.1084/jem.20040624

  101. 101.

    Berger E.A., McClellan S.A., Vistisen K.S. and Hazlett L.D. (2013 ) HIF-1α is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis. PLoS Pathog. 9, e1003457

    Not in our library10.1371/journal.ppat.1003457

  102. 102.

    Vissers M.C., Winterbourn C.C. and Hunt J.S. (1984 ) Degradation of glomerular basement membrane by human neutrophils in vitro. Biochim. Biophys. Acta 804, 154–160

    Not in our library10.1016/0167-4889(84)90144-7

  103. 103.

    Perez-Cruz I., Carcamo J.M. and Golde D.W. (2003 ) Vitamin C inhibits FAS-induced apoptosis in monocytes and U937 cells. Blood 102, 336–343

    Not in our library10.1182/blood-2002-11-3559

  104. 104.

    Ferron-Celma I., Mansilla A., Hassan L., Garcia-Navarro A., Comino A.M., Bueno P. et al. (2009 ) Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery. J. Surg. Res. 153, 224–230

    Not in our library10.1016/j.jss.2008.04.024

  105. 105.

    Uchio R., Hirose Y., Murosaki S., Yamamoto Y. and Ishigami A. (2015 ) High dietary intake of vitamin C suppresses age-related thymic atrophy and contributes to the maintenance of immune cells in vitamin C-deficient senescence marker protein-30 knockout mice. Br. J. Nutr. 113, 603–609

    Not in our library10.1017/s0007114514003857

  106. 106.

    Goldschmidt M.C. (1991 ) Reduced bactericidal activity in neutrophils from scorbutic animals and the effect of ascorbic acid on these target bacteria in vivo and in vitro. Am. J. Clin. Nutr. 54, 1214S–1220S

    Not in our library10.1093/ajcn/54.6.1214s

  107. 107.

    Gaut J.P., Belaaouaj A., Byun J., Roberts L.J. II, Maeda N., Frei B. et al. (2006 ) Vitamin C fails to protect amino acids and lipids from oxidation during acute inflammation. Free Radic. Biol. Med. 40, 1494–1501

    Not in our library10.1016/j.freeradbiomed.2005.12.013

  108. 108.

    Bozonet S.M., Carr A.C., Pullar J.M. and Vissers M.C. (2015 ) Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. Nutrients 7, 2574–2588

    Not in our library10.3390/nu7042574

  109. 109.
    Vitamin C: A Novel Regulator of Neutrophil Extracellular Trap Formation · 2013
    No notice
  110. 110.

    Groux H. and Powrie F. (1999 ) Regulatory T cells and inflammatory bowel disease. Immunol. Today 20, 442–445

    Not in our library10.1016/s0167-5699(99)01510-8

  111. 111.

    Shi L.Z., Wang R., Huang G., Vogel P., Neale G., Green D.R. et al. (2011 ) HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376

    Not in our library10.1084/jem.20110278

  112. 112.

    Dang E.V., Barbi J., Yang H.Y., Jinasena D., Yu H., Zheng Y. et al. (2011 ) Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784

    Not in our library10.1016/j.cell.2011.07.033

  113. 113.

    Doedens A.L., Phan A.T., Stradner M.H., Fujimoto J.K., Nguyen J.V., Yang E. et al. (2013 ) Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182

    Not in our library10.1038/ni.2714

  114. 114.

    Higashiyama M., Hokari R., Hozumi H., Kurihara C., Ueda T., Watanabe C. et al. (2012 ) HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis. J. Leukoc. Biol. 91, 901–909

    Not in our library10.1189/jlb.1011518

  115. 115.

    Flück K., Breves G., Fandrey J. and Winning S. (2016 ) Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis. Mucosal Immunol. 9, 379–390

    Not in our library10.1038/mi.2015.67

  116. 116.

    Hammami A., Abidin B.M., Heinonen K.M. and Stäger S. (2018 ) HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis. Sci. Rep. 8, 3500

    Not in our library10.1038/s41598-018-21891-z

  117. 117.
    An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression · 2017
    No notice
  118. 118.
    Targeted Deletion of HIF-1α Gene in T Cells Prevents their Inhibition in Hypoxic Inflamed Tissues and Improves Septic Mice Survival · 2007
    No notice
  119. 119.

    Labiano S., Melendez-Rodriguez F., Palazon A., Teijeira A., Garasa S., Etxeberria I. et al. (2017 ) CD69 is a direct HIF-1α target gene in hypoxia as a mechanism enhancing expression on tumor-infiltrating T lymphocytes. Oncoimmunology 6, e1283468

    Not in our library10.1080/2162402x.2017.1283468

  120. 120.

    Fraser R.C., Pavlovic S., Kurahara C.G., Murata A., Peterson N.S., Taylor K.B. et al. (1980 ) The effect of variations in vitamin C intake on the cellular immune response of guinea pigs. Am. J. Clin. Nutr. 33, 839–847

    Not in our library10.1093/ajcn/33.4.839

  121. 121.

    Kennes B., Dumont I., Brohee D., Hubert C. and Neve P. (1983 ) Effect of vitamin C supplements on cell-mediated immunity in old people. Gerontology 29, 305–310

    Not in our library10.1159/000213131

  122. 122.

    Huijskens M.J., Walczak M., Koller N., Briede J.J., Senden-Gijsbers B.L., Schnijderberg M.C. et al. (2014 ) Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells. J. Leukoc. Biol. 96, 1165–1175

    Not in our library10.1189/jlb.1ta0214-121rr

  123. 123.

    Huijskens M.J., Walczak M., Sarkar S., Atrafi F., Senden-Gijsbers B.L., Tilanus M.G. et al. (2015 ) Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy 17, 613–620

    Not in our library10.1016/j.jcyt.2015.01.004

  124. 124.

    Manning J., Mitchell B., Appadurai D.A., Shakya A., Pierce L.J., Wang H. et al. (2013 ) Vitamin C promotes maturation of T-cells. Antioxid. Redox Signal. 19, 2054–2067

    Not in our library10.1089/ars.2012.4988

  125. 125.

    Wu X. and Zhang Y. (2017 ) TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18, 517–534

    Not in our library10.1038/nrg.2017.33

  126. 126.

    Blaschke K., Ebata K.T., Karimi M.M., Zepeda-Martinez J.A., Goyal P., Mahapatra S. et al. (2013 ) Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500, 222–226

    Not in our library10.1038/nature12362

  127. 127.

    Minor E.A., Court B.L., Young J.I. and Wang G. (2013 ) Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J. Biol. Chem. 288, 13669–13674

    Not in our library10.1074/jbc.c113.464800

  128. 128.

    Hore T.A. (2017 ) Modulating epigenetic memory through vitamins and TET: implications for regenerative medicine and cancer treatment. Epigenomics 9, 863–871

    Not in our library10.2217/epi-2017-0021

  129. 129.

    Tsukada Y., Fang J., Erdjument-Bromage H., Warren M.E., Borchers C.H., Tempst P. et al. (2006 ) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816

    Not in our library10.1038/nature04433

  130. 130.

    Klose R.J., Kallin E.M. and Zhang Y. (2006 ) JmjC-domain-containing proteins and histone demethylation. Nat. Rev. Genet. 7, 715–727

    Not in our library10.1038/nrg1945

  131. 131.

    Cull A.H., Snetsinger B., Buckstein R., Wells R.A. and Rauh M.J. (2017 ) Tet2 restrains inflammatory gene expression in macrophages. Exp. Hematol. 55, 56–70.e13

    Not in our library10.1016/j.exphem.2017.08.001

  132. 132.

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    Foster M.N., Carr A.C., Antony A., Peng S. and Fitzpatrick M.G. (2018 ) Intravenous vitamin C administration improved blood cell counts and health-related quality of life of patient with history of relapsed acute myeloid leukaemia. Antioxidants 7, E92

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    Zhao H., Zhu H., Huang J., Zhu Y., Hong M., Zhu H. et al. (2018 ) The synergy of vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Leuk. Res. 66, 1–7

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    Zhang X., Ulm A., Somineni H.K., Oh S., Weirauch M.T., Zhang H.X. et al. (2014 ) DNA methylation dynamics during ex vivo differentiation and maturation of human dendritic cells. Epigenetics Chromatin 7, 21

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    Ptaschinski C., Mukherjee S., Moore M.L., Albert M., Helin K., Kunkel S.L. et al. (2015 ) RSV-induced H3K4 demethylase KDM5B leads to regulation of dendritic cell-derived innate cytokines and exacerbates pathogenesis in vivo. PLoS Pathog. 11, e1004978

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    5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4+ T Cells · 2016
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    Ichiyama K., Chen T., Wang X., Yan X., Kim B.S., Tanaka S. et al. (2015 ) The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 42, 613–626

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    Carty S.A., Gohil M., Banks L.B., Cotton R.M., Johnson M.E., Stelekati E. et al. (2018 ) The loss of TET2 promotes CD8+ T cell memory differentiation. J. Immunol. 200, 82–91

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    McPherson R.C., Konkel J.E., Prendergast C.T., Thomson J.P., Ottaviano R., Leech M.D. et al. (2014 ) Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4+ T cells tolerized by peptide immunotherapy. eLife 3, e03416

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    LaMere S.A., Thompson R.C., Meng X., Komori H.K., Mark A. and Salomon D.R. (2017 ) H3k27 methylation dynamics during CD4 T cell activation: regulation of JAK/STAT and IL12RB2 expression by JMJD3. J. Immunol. 199, 3158–3175

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    Wei G., Wei L., Zhu J., Zang C., Hu-Li J., Yao Z. et al. (2009 ) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167

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    Li Q., Zou J., Wang M., Ding X., Chepelev I., Zhou X. et al. (2014 ) Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat. Commun. 5, 5780

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    Yue X., Trifari S., Aijo T., Tsagaratou A., Pastor W.A., Zepeda-Martinez J.A. et al. (2016 ) Control of Foxp3 stability through modulation of TET activity. J. Exp. Med. 213, 377–397

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    Sasidharan Nair V., Song M.H. and Oh K.I. (2016 ) Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner. J. Immunol. 196, 2119–2131

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    Nikolouli E., Hardtke-Wolenski M., Hapke M., Beckstette M., Geffers R., Floess S. et al. (2017 ) Alloantigen-induced regulatory T cells generated in presence of vitamin C display enhanced stability of Foxp3 expression and promote skin allograft acceptance. Front. Immunol. 8, 748

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    Kasahara H., Kondo T., Nakatsukasa H., Chikuma S., Ito M., Ando M. et al. (2017 ) Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model. Int. Immunol. 29, 457–469

    Not in our library10.1093/intimm/dxx060

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    Song M.H., Nair V.S. and Oh K.I. (2017 ) Vitamin C enhances the expression of IL17 in a Jmjd2-dependent manner. BMB Rep. 50, 49–54

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    Tsagaratou A., Gonzalez-Avalos E., Rautio S., Scott-Browne J.P., Togher S., Pastor W.A. et al. (2017 ) TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells. Nat. Immunol. 18, 45–53

    Not in our library10.1038/ni.3630

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    Not in our library10.1038/ni.3644

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    Bhandari T., Olson J., Johnson R.S. and Nizet V. (2013 ) HIF-1alpha influences myeloid cell antigen presentation and response to subcutaneous OVA vaccination. J. Mol. Med. 91, 1199–1205

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    Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility · 2016
    No notice
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    Maeng H.G., Lim H., Jeong Y.J., Woo A., Kang J.S., Lee W.J. et al. (2009 ) Vitamin C enters mouse T cells as dehydroascorbic acid in vitro and does not recapitulate in vivo vitamin C effects. Immunobiology 214, 311–320

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    Noh K., Lim H., Moon S.K., Kang J.S., Lee W.J., Lee D. et al. (2005 ) Mega-dose Vitamin C modulates T cell functions in Balb/c mice only when administered during T cell activation. Immunol. Lett. 98, 63–72 PMID:

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    Puskas F., Gergely P., Niland B., Banki K. and Perl A. (2002 ) Differential regulation of hydrogen peroxide and Fas-dependent apoptosis pathways by dehydroascorbate, the oxidized form of vitamin C. Antioxid. Redox Signal. 4, 357–369 PMID:

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    Shilotri P.G. (1977 ) Phagocytosis and leukocyte enzymes in ascorbic acid deficient guinea pigs. J. Nutr. 107, 1513–1516 PMID:

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    Vissers M.C. and Hampton M.B. (2004 ) The role of oxidants and vitamin C on neutrophil apoptosis and clearance. Biochem. Soc. Trans. 32, 499–501

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    Vissers M.C. and Wilkie R.P. (2007 ) Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1alpha. J. Leukoc. Biol. 81, 1236–1244

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    Vojdani A. and Ghoneum M. (1993 ) In vivo effect of ascorbic acid on enhancement of human natural killer cell activity. Nutr. Res. 13, 753–764

    Not in our library10.1016/s0271-5317(05)80799-7

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