Abstract
Vitamin C plays a multifaceted role in various biological processes and is well-known to facilitate pleiotropic activities in both innate and adaptive immune responses, where the antioxidant capacity of vitamin C is most likely highly relevant since immune responses mainly occur in reducing environments. Beyond its antioxidant properties, vitamin C can enhance the transcription potential of genes by promoting DNA demethylation through ten-eleven-translocation (Tet) methylcytosine dioxygenases, which have been recently demonstrated to be critical for the development and differentiation of T cells. In this minireview, we will provide a broader overview on the impact of vitamin C on signaling and regulatory activities in both innate and adaptive immune cells. Particularly, we will summarize recent findings on the decisive role of finely tuned vitamin C concentrations for T cell development, T helper cell differentiation, and optimal T cell-mediated immune responses.
Overview on impact of vitamin C on innate and adaptive immune cells
The human body needs to receive a sufficient amount of nutrients in order to maintain a healthy immune system [1]. Nutritional deficits disrupt both innate and adaptive immune responses by creating an immune imbalance, resulting in dysregulated host immune responses towards pathogens. Vitamin C is an important nutritional antioxidant that protects the immune system against the deleterious effects of reactive oxygen species (ROS) [2]. Despite being one of the most vital nutrients, vitamin C cannot be stored by the body, so it is necessary to maintain optimal vitamin C levels through dietary intake [3, 4]. On the other hand, intolerable uptake can cause more damage than benefit [5–7]. There are two forms of vitamin C: a reduced form, ascorbic acid or ascorbate, which is taken up into cells by sodium-dependent vitamin C transporters (SVCT-1 and -2) [8], and an oxidized form, dihydroascorbic acid (DHA), which is transported by glucose transporters (GLUT-1, -3 and -4) [9]. In blood and body fluids, a greater fraction of vitamin C is present in its reduced form, while DHA contributes to less than 10% of vitamin C. It has been reported that SVCT1 transports vitamin C via the intestinal barrier, while SVTC2 carries vitamin C from the blood into cells [8, 10, 11].
Intracellular communication for adequate immune responses becomes critical in an oxidative stress environment, causing systemic inflammation by disrupting immune homeostasis [12]. A critical balance must be maintained between oxidant and antioxidant mechanisms in order to suppress excessive ROS production [13]. During infectious conditions, inflammatory cells release higher ROS levels, leading to a greater neutrophil infiltration and imbalance between neutrophils and lymphocytes [14–16]. Additionally, plasma membranes of immune cells contain a high percentage of polyunsaturated fatty acids that produce excessive ROS for their normal function, making cells highly susceptible to oxidative damage [17]. Consequently, the antioxidant characteristics of ascorbic acid strengthen immune responses in multiple ways, including activating phosphatases to enhance cellular function [18], activating the activating protein-1 (AP-1) transcription factor to enhance proliferation and differentiation of immune cells [19], and enhancing active DNA demethylation to regulate gene expression through ten-eleven-translocation (Tet) methylcytosine dioxygenases (Fig. 1) [20].
Tet enzymes influence the DNA methylation landscape by supporting the active demethylation of 5-methylcytosine to cytosine. Ten-eleven translocation (Tet) enzymes first convert 5-methylcytosine to 5-hydroxymethylcytosine. Next, 5-hydroxymethylcytosine is further oxidized to 5-formylcytosine and 5-carboxylcytosine. Finally, 5-formylcytosine and 5-carboxylcytosine are converted to cytosine by the base excision repair pathway enzyme, thymine DNA glycosylase (TDG). Created with BioRender.com
Citation: European Journal of Microbiology and Immunology 14, 2; 10.1556/1886.2024.00017
Despite the fact that the role of antioxidants in the immune response still remains incompletely understood, it is generally accepted since many years that reducing free radicals can prevent immune cells from sustained DNA damage [21] and that vitamin C plays an indispensable role in protecting neutrophils against the toxic effects of superoxide anions [22]. Indeed, vitamin C plays a crucial role in reducing free radical damage and modulates immune cell function along with other nutrients [23]. Mechanistically, it has been suggested that vitamin C has the potential to reduce ROS-mediated oxidative stress to lymphocytes by stimulating the production of vitamin E [24]. The antioxidant property of vitamin C also relies on the reduction of ROS-mediated expression of proinflammatory cytokines including interleukin (IL)- 1 and tumor necrosis factor alpha (TNFα) by inhibiting nuclear factor kappa B (NF-kB) transcription [25]. The impact of ascorbic acid on T cells has also been verified through reports, suggesting that it strengthens antioxidant-mediated immunity and enhances the antigen-specific response of T cells, indicating the potential of vitamin C for altering immune responses [26, 27]. Notably, a suboptimal reduction in antioxidants can impair immunosuppression by inducing T cell apoptosis. This was confirmed by a study conducted on thymocyte apoptosis with various concentrations of vitamin C and concluded that higher concentrations significantly modulate spontaneous T cell apoptosis [28]. Aside from T cells, vitamin C can also inhibit CD95-induced death of human monocytes [29], and higher doses of vitamin C enhance natural killer (NK) cell cytotoxicity without affecting apoptosis [30]. Additionally, the use of vitamin C has been shown in a clinical study to increase NK cell activity in response to toxic chemical exposure by augmenting the enzymatic activity of protein kinase C [31]. Altogether, these reports suggest that vitamin C can modulate the innate and adaptive immune system by regulating apoptosis signaling.
In the next sections, this review will focus on the effects of vitamin C on T cell development, helper T (Th) cell differentiation, and optimal T cell-mediated immune responses, omitting the underlying molecular mechanisms, which have already been thoroughly reviewed elsewhere. For instance, there are seminal reports addressing the molecular mechanisms behind vitamin C's effect on lymphocytes [26, 32–34].
Impact of vitamin C on the development of T cells
Foreign antigens are recognized by T cells via T cell receptors (TCRs) as short peptides bound to major histocompatibility complex (MHC) class I or class II proteins. The specificity of these TCRs for their ligands is unpredictable as they develop through random somatic DNA rearrangements. Optimal TCR signaling involves co-engagement with either a CD4 (supporting MHC class II recognition) or CD8 (supporting MHC class I recognition) co-receptor. Unlike immature thymocytes, mature functional T cells express a co-receptor that matches their MHC class specificity. CD4+CD8+ double-positive (DP) thymocytes differentiate during thymic T cell development into either cytotoxic (CD8+) or helper (CD4+) subsets of T cells. Two models have been put forward to demonstrate the MHC binding characteristics of TCR and co-receptors [35]. In the instruction model, signals mediated via binding of CD4 and the TCR to MHCII differ from those mediated by binding of CD8 and the TCR to MHCI, allowing precursor DP thymocytes to choose between CD4 and CD8 lineages. The 'strength of signal' model suggests that cell lineage choice is determined by the duration and intensity of a primary signal. Prolonged strong signaling poises to CD4 lineage development, while shorter and weaker signals favor CD8 lineage choice.
It has been reported that vitamin C plays a significant role in the transition of thymic CD4−CD8− double-negative (DN) precursors to the DP stage in feeder-free culture systems [32]. Further, it was demonstrated both in vitro and in vivo that vitamin C enhances the early maturation of thymocytes in a dose-dependent manner [32]. Importantly, the ascorbic acid-mediated maturation of thymocytes depends on a cell-intrinsic mechanism rather than on effects on TCR rearrangement. However, vitamin C is also involved in the selection of functional TCRαβ pairs after the β-selection stage [32]. Reports showed that ascorbic acid supplementation increases zeta-chain-associated protein kinase 70 (ZAP70) expression, a kinase crucially involved in T cell signaling and the development of CD8 single-positive (SP) cells [32, 36]. Moreover, vitamin C supplementation along with inhibition of DNA and histone methylation promote the transition from DN to DP thymocytes [32]. Together, these reports confirm that vitamin C contributes to improving the overall efficiency of TCR-mediated signaling pathways, making it a key player for the selection processes during T cell development.
Role of vitamin C in Th cell differentiation
CD4+ T helper cells, also known as Th cells, play a vital role in ensuring that the body's defense mechanisms are both precise and effective against pathogens. An important function of Th cells is to recognize antigens presented by antigen-presenting cells and undergo activation and clonal expansion. Th cells exhibit remarkable functional diversity and differentiate into distinct subsets that are categorized based on their lineage-specification factor expression, cytokine secretion profiles and unique effector functions into Th1, Th2, Th17 cells and Tregs, amongst others [37]. Recent evidence suggests that vitamin C plays a decisive role during the differentiation of Th cells, confirmed through both in vivo and in vitro models (Fig. 2) [33].
Direct and indirect impact of vitamin C on Th cell differentiation. A) Upon antigen-specific activation via antigen-presenting cells (APCs), naïve CD4+ T cells can differentiate into various Th cell subsets. Vitamin C is directly impacting Th cell differentiation as summarized in the text boxes. B) Vitamin C can also indirectly affect Th1 cell differentiation by modulating cytokine expression of dendritic cells as indicated in the text box. Created with BioRender.com
Citation: European Journal of Microbiology and Immunology 14, 2; 10.1556/1886.2024.00017
It has been shown that at optimal concentrations, vitamin C facilitates proliferation and survival of T cells and enhanced their functionality [38, 39]. Indeed, vitamin C could target oxidative stress and helped to maintain immunological memory by boosting the commitment of naive T cells to long-living memory T cells upon ageing, yet excessive consumption of antioxidants could cause detrimental effects [40]. Reports showed that vitamin C treatment decreased the number of IL-2-producing T cells, but not the number of interferon (IFN) γ- and TNFα-producing cells [41]. Notably, higher vitamin C concentrations adversely affect T-cell viability, resulting in decreased production of cytokines such as TNFα, IFNγ and IL-4 [42].
A meta data analysis showed that in mouse allergic models, administration of high vitamin C doses results in less severe inflammation with a shift from Th2 towards Th1 cytokine profiles, namely increased IFNγ and less IL-4 production [43]. The treatment with vitamin C also reduced the production of pro-inflammatory cytokines like TNFα and IL-1 through ROS-dependent inhibition of NF-κB [43]. In addition to the modulation of pro-inflammatory cytokines, vitamin C also promoted the secretion of the immunosuppressive cytokine IL-10 by dendritic cells (DCs), which in turn inhibits the production of pro-inflammatory cytokines [44]. Likewise, vitamin C inhibited the NF-κB dependent production of IL-6, which is a cytokine known to promote inflammatory responses [45].
Accumulating evidence suggests that vitamin C promotes a switch from Th2 to Th1 immunity. Among these reports, a dose-dependent study was conducted on delayed hypersensitivity responses to 2,4,-dinitro-I-fluorobenzene (DNFB). Notably, a significant difference in the differentiation of T cells was observed in the administration of vitamin C “during” sensitization and “before or after” sensitization with DNFB. A higher level of Th1 and a lower level of Th2 cytokines was observed in the former case, however these results were nullified in the latter case [46]. Furthermore, another study examining the effects of vitamin C supplementation on asthma also observed a shift in immune balance from Th2 to Th1 cells. Here, supplementation of vitamin C on asthma model mice showed a significant increase in the IFNγ to IL-5 secretion ratio in bronchoalveolar lavage fluid [47]. While it has not been elucidated how this shift is orchestrated, DCs have been speculated to play a significant role. According to an in vitro study with murine bone marrow-derived DCs that were activated with lipopolysaccharide (LPS), vitamin C pre-treatment resulted in higher levels of Th1 cytokines, including IL-12 and IFNγ, and diminished production of IL-5 [48]. Despite these findings, vitamin C appears to have the greatest impact on T cell differentiation as a direct effect on T cells. It has been reported that vitamin C acts as a cofactor for the Jumonji C domain-containing histone lysine demethylases (JmjC-KDMs), which play a pivotal role in cellular differentiation of Th17 cells [49, 50]. Additionally, histone methylation patterns were found to be crucial to the stability of Th17 cells [51]. The Jumonji domain-containing protein-3 (Jmjd3), another epigenetic regulator, was found to directly interact with the retinoic acid-receptor (RAR)-related orphan receptor C (RORC) locus, encoding for the Th17 lineage-specification factor RORγt, resulting in reduced lysine 27 on histone H3 (H3K27) tri-methylation levels [52]. Under Th17 cell polarization conditions, vitamin C has also been shown to enhance Th17 cell differentiation through the upregulation of the histone demethylating activity of Jmjd2 (KDM4A) [53]. Finally, vitamin C reduced lysine 9 on histone H3 (H3K9) tri-methylation levels, a transcriptional inhibition histone mark, within the IL17 locus and consequently resulted in increased IL-17 production [53].
The regulatory T cells (Tregs) play an essential role in immunological tolerance [54]. Tregs, which are characterized by the expression of the transcription factor forkhead box P3 (Foxp3), can efficiently suppress the activity of other immune cells, which helps to maintain homeostasis, avoid autoimmune diseases and prevent overshooting immune responses and tissue damage by regulating the release of inflammatory cytokines. Tregs are classified in thymic Tregs (tTregs), generated already in the thymus during T cell development, peripherally-induced Tregs (pTregs), which are generated by the conversion of naive CD4+ T cells into Foxp3+ Tregs in the periphery, and in vitro induced Tregs (iTregs).
Vitamin C has been demonstrated as a crucial epigenetic remodeler that affects the generation and maintenance of iTregs by enhancing and stabilizing Foxp3 expression [55]. Vitamin C facilitates Tet-mediated active DNA demethylation of the conserved noncoding sequence 2 (CNS2) of the Foxp3 locus, also named Treg-specific demethylated region (TSDR). In the CNS2 locus of iTregs, 5 mC was modified to 5hmC and eventually converted to unmethylated cytosine, in order to stabilize Foxp3 [55]. These conversions of 5 mC to unmethylated cytosine (Fig. 1) were accelerated by vitamin C in a Tet2-dependent manner [55]. Interestingly, the expression of the vitamin C transporter, SVCT2, was found to be at the highest level in Tregs when compared to other immune cell subsets [56]. Yet, unexpectedly vitamin C treatment adversely affected the ability of ex vivo isolated Tregs to suppress effector T cell proliferation in vitro, while having an enhancing effect in iTregs [56]. Also, the impact of vitamin C on Treg-mediated immune response in vivo remains controversially discussed. Even though vitamin C improved the generation of iTregs both in vivo and in vitro, no enhanced allograft tolerance was observed in one study, in which animals were treated orally with vitamin C [56]. In contrast, another report investigating in vitro generated alloantigen-specific Tregs observed an enhanced Foxp3 stability accompanied with a pronounced TSDR demethylation upon addition of vitamin C to the cultures, and also demonstrated a more effective suppressive function when analyzed in vivo in a highly immunogenic skin transplantation model [57]. Together, these reports suggest that vitamin C can affect Th cell differentiation by either directly acting on T cells or via modulating the functional properties of accessory cells like DCs. Indeed, a murine study showed that DCs treated with vitamin C secrete more IL-12p70, promoting Th1 cell differentiation and boosting IFNγ production by T cells [48]. Further research is needed to fully understand the role of vitamin C treated DCs in other Th subsets. Moreover, it has been recently demonstrated that during the maturation of DCs, vitamin C initiated the profound demethylation of NF-κB/p65 binding sites and stimulated the expression of immune response/antigen presentation-related genes in a Tet2-dependent manner [58]. Additionally, vitamin C further enhanced the secretion of tumor necrosis factor beta (TNFβ) in DCs in a NF-κB-dependent manner and upregulated its expression by demethylating adjacent CpG motifs.
Potential therapeutic applications of vitamin C in T cell-mediated and other inflammatory diseases
It is widely accepted that vitamin C is necessary for the proper function of several immune system elements, and the recent observation that vitamin C can affect CD4+ T helper cell differentiation suggests that it can also affect the outcome of T cell-mediated diseases. During infection with malaria, oral vitamin C administration has also been shown to regulate the host's immune response. Upon vitamin C supplementation, both activated Th1 cells and macrophages were increased in numbers when compared to the untreated group, with a reduction in TNFα secretion [59]. Further, a higher percentage of matured DCs in the vitamin C-treated group suggested that vitamin C was capable of enhancing the host immune responses [59]. The increased production of IFNγ, IL-2, and IL-12 further demonstrated the role of vitamin C in activating the host immune system against malaria [59]. This indicates that vitamin C could be an effective adjunct to conventional antimalarial therapies by augmenting protective immune responses. In zoonotic infections, such as rabies, vitamin C administration has likewise been found to increase the levels of respective Th1 and Th2 cytokines, including IFNγ, IL-4, and IL-5 in vaccinated mice [60]. This suggests that vitamin C could be beneficial in enhancing vaccine-induced protective immunity against zoonotic infections.
In Crohn's disease patients receiving oral vitamin C supplementation, T-cell hyporesponsiveness was reversed, while no effect was found on humoral immunity, suggesting that vitamin C plays a much more pivotal role in cell-mediated immunity than humoral immunity [61]. Another study confirmed this hypothesis by showing a synergetic effect of vitamin C and other micronutrients on T cell-mediated enhancement of skin barrier function without any involvement of antibody-mediated protection [61]. In contrast, an animal study report demonstrated that vitamin C supplements play a vital role in humoral immunity since they increased serum levels of antibodies in guinea pigs that cannot produce vitamin C and must be dietary supplemented [62]. Furthermore, vitamin C supplementation was frequently reported to reduce sepsis and sepsis-induced multiple organ disorder syndrome [63]. In response to an infection, the host releases elevated levels of both pro-inflammatory and anti-inflammatory cytokines during sepsis [64], and vitamin C supplements have been found to decrease the production of pro-inflammatory cytokines, thus balancing inflammatory responses during the course of disease [65, 66]. In cancer patients, intravenous administration of high vitamin C dosage reduced the production of pro-inflammatory cytokines including IL-1α, IL-2, IL-8, and TNFα and also of the chemokine eotaxin [67]. This report demonstrated that high doses of intravenous ascorbate may reduce inflammation in patients with cancer. Compared to normal cells, cancer cells have a higher metabolic rate and defective mitochondria, which makes them more susceptible to oxidative stress [68]. Higher dosages of vitamin C may be an effective pro-oxidant therapy for cancer cells because they possess significant amounts of labile transition metals [69] and are more dependent on glycolysis [70]. Additionally, vitamin C serves as a potential natural compound that hinders tumor progression through various mechanisms, including pro-oxidant, hypoxia-inducible factor-1 (HIF1) signaling and Tet enzyme activation [71]. In addition to maintaining the redox potential of cells, vitamin C protects them from ROS produced during respiratory bursts and inflammatory responses [72]. Thus, vitamin C not only plays a role in anti-oxidation during inflammation, but also functions as a cofactor for various enzymes, and also contributes to tissue integrity and skin regeneration [73]. Furthermore, a study on multiple myeloma and lymphoma patients who received autologous hematopoietic stem cell transplantation along with vitamin C treatment showed higher frequencies of both NK and CD3+ T cells, and also a lower infection rate [74].
Conclusion
The comprehensive analysis of the functional properties of vitamin C reveals that beyond its well-known antioxidant properties it exerts a substantial influence on CD4+ Th cell differentiation. The intricate interplay between vitamin C and the molecular mechanisms governing Th cell fate decisions holds promise for therapeutic interventions targeting immune-related disorders. Clinical studies and trials investigating the impact of vitamin C on T cells reveal a promising connection between vitamin C supplementation and immune modulation. While challenges persist, the findings underscore the potential of vitamin C as a modulator of T cell development, differentiation and function. As research in this field progresses, a deeper understanding of vitamin C's role in shaping adaptive, T cell-mediated immune responses may open new avenues for personalized approaches to immune modulation.
Funding sources
This research was funded by Friend of HZI Foundation, stipend to VS.
Authors' contribution
Both VS and JH wrote the review article.
Conflicts of interest
The authors declare no conflicts of interest.
List of abbreviations
| APC | antigen-presenting cells |
| AP-1 | activating protein-1 |
| CNS2 | conserved noncoding sequence 2 |
| DC | dendritic cells |
| DHA | dihydroascorbic acid |
| DN | double-negative thymocytes |
| DNFB | 2,4,-dinitro-I-fluorobenzene |
| DP | double-positive thymocytes |
| Foxp3 | forkhead box P3 |
| GLUT | glucose transporters |
| H3K27 | lysine 27 on histone H3 |
| H3K9 | lysine 9 on histone H3 |
| HIF1 | hypoxia-inducible factor-1 |
| IFN | interferon |
| IL | interleukin |
| iTregs | in vitro induced Tregs |
| JmjC-KDM | jumonji C domain-containing histone lysine demethylases |
| LPS | lipopolysaccharide |
| MHC | major histocompatibility complex |
| NF-kB | nuclear factor kappa B |
| NK | natural killer cells |
| pTregs | peripherally-induced Tregs |
| ROR | retinoic acid-receptor (RAR)-related orphan receptor |
| ROS | reactive oxygen species |
| SP | single-positive thymocytes |
| SVCT | sodium-dependent vitamin C transporters |
| TCR | T cell receptor |
| TET | ten-eleven-translocation |
| Th | helper T |
| TNF | tumor necrosis factor |
| Tregs | regulatory T cells |
| TSDR | Treg-specific demethylated region |
| tTregs | thymic Tregs |
| ZAP70 | zeta-chain-associated protein kinase 70 |
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