Review Article | Open Access
The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator?
Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.
Natural killer T (NKT) cells are a component of the innate immune system, which initiate and refine innate and adaptive immune responses. NKT cells can be subdivided into type 1 and type 2 NKT cells based on their T cell receptors (TCR), with type 1 NKT cells being commonly known as invariant NKT (iNKT) cells [1–3]. These two types of NKT cells display distinct roles involved in either the promotion or control of immune responses . The role of iNKT cells and their mediators has been well defined in several conditions, including some autoimmune diseases such as multiple sclerosis (MS) . However, the role of iNKT cells in other autoimmune conditions remains largely unexplored.
The liver’s immune system is particularly specialized in dealing with exposure to dietary and commensal microbial antigens, to which it must remain tolerant. Hepatic immune tolerance is modulated by antigen-presenting cells, such as dendritic cells, Kupffer cells, hepatic stellate cells, and liver endothelial cells . The role of these populations is to constantly present harmless antigens to T cells and facilitate their commitment to apoptosis, anergy, or differentiation into regulatory T cells. Still, the liver is also able to respond to pathogenic stimuli and is equipped with cellular machinery to override immune tolerance. A variety of innate lymphocytic populations, including NKT cells, γδ T cells, mucosal-associated invariant T cells, and CD56(+) natural killer (NK) cells are resident or can rapidly accumulate in the hepatic microenvironment following potential pathogenic challenge [7, 8]. These cells can maintain or override hepatic immune tolerance to autoantigens, leading to expansion of autoreactive T cells that mediate liver injury causing autoimmune liver disease or direct liver injury by killing hepatocytes or bile duct cells [9, 10].
Autoimmune liver diseases (AiLD) include primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC) [28, 29]. Hepatocytes are the target of autoimmune attack in AIH, whereas the biliary epithelial cells are the targets in PBC and PSC . In PBC, the small- and medium-sized bile ducts are affected, as opposed to the larger bile ducts in PSC . The demographic, epidemiological, and clinical characteristics of these three conditions are distinct, and a variety of genetic , immunological, and environmental factors have been implicated in the disease development [32–43].
This review will examine the current knowledge regarding the role of iNKT cells in AiLD. We will first provide a general overview and update of iNKT cells function in other conditions as well as in experimental models. We will also discuss the emerging role of vitamin D in iNKT cells immunomodulation, which may serve as a therapeutic target [44–46].
2. Subtypes of NKT Cells and an Overview of Their Behavior
NKT cells are subdivided into type 1 (iNKT) and type 2 (NKT). iNKT cells are innate immune T cells that express the T cell receptor (TCR) Vα24-Jα18/Vβ11, natural killer (NK) cell surface markers (such as NK1.1, Ly149, CD161 and CD56), and activation markers CD25, CD69, and CD122 [47–51]. Liver iNKT cells have been recently shown to constitutively express the costimulatory tumor necrosis factor superfamily receptor OX40 . Memory NK-like T cell populations also exist in peripheral blood such as CD8(+) T cells responding to innate IL-12 and IL-18 stimulation and coexpressing the transcription factor Eomesodermin (Eomes) and KIR/NKG2A membrane receptors . Additionally, murine iNKT cells can express certain toll-like receptors (TLR), which facilitate TLR costimulation of iNKT cells in the presence of suboptimal concentrations of TCR agonists enhancing their cellular activation .
NKT cells recognize host and microbial lipid and/or alpha-mannosyl glycolipid antigens via CD1d (MHC class I-like molecule) through their TCR [55–57]. Activated NKT cells secrete Th1 cytokines (including IFN-γ and TNF-α), Th2 cytokines (such as IL-4 and IL-10), and Th17 cytokines (namely, IL-17 and IL-22) . Hence, NKT cells play an important role in immune system regulation by polarizing Th1, Th2, Th17, and Treg cells. iNKT cells also appear to have effects on B cells, NK cells, and dendritic cells (DCs) [59–61]. Innate immunity receptors within APCs, such as DCs, activate iNKT cells through the combined presentation of lipids by CD1d and production of proinflammatory cytokines, such as IL-12 and type I IFNs . Innate receptors include TLRs, Nod-like receptors (NLRs), Rig-I-like receptors (RLRs), and C-type lectin-like receptors .
NKT cells display both proinflammatory and anti-inflammatory behaviors, with iNKT cells generally being proinflammatory and type 2 NKT cells being suppressors of inflammation. However, recent data also indicates a possible role of type 2 NKT cells in promoting chronic inflammation [64, 65]. Hence, these roles may be reversed in differing pathological states . For example, iNKT cells appear to have suppressive behavior in both experimental autoimmune encephalomyelitis (EAE) animal model and patients with MS [66, 67] but an inflammatory role in allergen-induced airway disease [60, 68–70]. iNKT cells cytokine/chemokine production has been shown to be chemoattractant to neutrophils and macrophages in organs such as the liver [9, 71]. Opposing roles for iNKT and type 2 NKT cells have been proposed in autoimmunity [72, 73]. Generally speaking, iNKT cells are believed to have a predominantly proinflammatory role [73–78], although they have also been observed to secrete IL-4 after stimulation with alpha-galactosylceramide (-GalCer) [9, 71, 79]. Type 2 NKT cells (which are sulfatide-reactive [50, 51, 80]) have been shown to be anti-inflammatory and appear to inhibit iNKT cells function [9, 75]. Transfer of DCs from sulfatide-treated animals to naïve recipients resulted in iNKT cells anergy .
Despite some experimental studies demonstrating opposing roles for iNKT and type 2 NKT cells, several other studies have shown dual proinflammatory and anti-inflammatory roles for iNKT cells. An anti-inflammatory role has been proposed for iNKT cells in Chagas disease, whereas type 2 NKT cells were found to be inflammatory/pathogenic . In a murine model of Schistosomiasis, a proinflammatory role via Th1 cytokines has been described for iNKT cells, whereas type 2 NKT cells act via a Th2 response . Miyazaki et al.  noticed decreased levels of mucosal associated iNKT cells in the peripheral blood of patients with MS, which were especially reduced during relapses. Invariant NKT cells levels reflected disease activity with decreasing iNKT cells in MS flares . Levels of iNKT cells increased with clinical recovery . Other studies have reported similar findings in experimental autoimmune encephalomyelitis (EAE), whereby activating iNKT cells with -GalCer modulated the disease course [84–87]. The anti-inflammatory role by iNKT cells is believed to be due to IL-4 and IL-10 secretion, which promotes a deviation to a Th2 cytokine response , although a role for IFN-γ has also been postulated [88, 89]. Other studies note protection from autoimmune disease following iNKT cells stimulation by -GalCer in NOD mice [90, 91]. Invariant NKT cells have also been implicated in the progression of several autoimmune conditions, indicating differing roles of iNKT cells in various disorders [8, 24, 92–94].
3. iNKT Cells and B Cell Regulation
Current research indicates a regulatory role of iNKT cells over B cells, which is dependent on the interaction of iNKT cells with B cells via CD1d, which may be IL-4-driven [95–98]. It appears that iNKT cells are recruited to activate B cells in response to antigenic lipids, thus enhancing antibody response . Recent studies in mice, however, have shown that iNKT cells stimulation culminated in the rapid activation and hepatic recruitment of innate-like regulatory B cells [100, 101]. Regulatory B cells (Bregs) influence immune responses primarily, although not exclusively, via the production of IL-10. The importance of human Bregs in the maintenance of immune homeostasis has been documented in several autoimmune-related pathologies [102–105].
It has also been found that marginal zone B cells are capable of activating iNKT cells [106, 107]. Bialecki and colleagues  found that marginal zone B cells sensitized with -GalCer activated iNKT cells hybridomas but were unable to directly activate ex vivo sorted iNKT cells in the absence of DCs in culture. DC activation of iNKT cells was enhanced by marginal zone B cells and reduced in their absence . It was also found that in vivo transfer of -GalCer loaded marginal zone B cells activated both iNKT and NK cells .
The role of iNKT cells with regard to antibody production appears to be diverse, with some studies indicating an enhancement of antibody/autoantibody production via iNKT cells, whereas others note a reduction. This may be due to differing action of iNKT cells subtypes. It has been noted that CD1d deficiency in animal models exacerbates autoantibody production . Wermeling et al.  injected murine models with apoptotic cells to trigger autoantibody production and found that reduced or absent iNKT cells resulted in increased autoreactive B cell activation, which was also observed in models where CD1d expression was absent on B cells. In response to injected apoptotic cells, iNKT cells upregulated the activation marker CD69, in association with decreased IFN-γ but increased IL-10 production . However, IFN-γ was increased in NK cells and CD4+ T cells . In splenic CD1d -/- CD45.1-B cells (GL7hi and CD95hi), IgM and IgG3 anti-DNA production was increased in association with increased survival of those B cells . A second animal model with a 50% reduction in iNKT cells (Jα18+/-) showed increased IgG anti-DNA and splenic germinal center B cell levels, and repopulation with iNKT cells resulted in decreased IgG3 anti-DNA production and a decreased percentage of germinal center B cells . Yang et al.  reported similar findings, where iNKT cells suppressed IgG anti-DNA Ab and rheumatoid factor production but increased total IgG production and enhanced activation markers on B cells. That study also found that both autoreactive and nonautoreactive B cells were activated by iNKT cells, with autoreactive B cells expressing higher levels of CD1d .
Differing biological actions of iNKT cells subsets influence differential B cell function. An earlier study by Galli et al.  established that immunizing mice with -GalCer and proteins resulted in increased antibody titers compared to immunization with protein alone and that decay of circulating antibodies occurred more rapidly in iNKT cells-deficient mice. These observations have also been noted in additional studies [110–113]. Galli et al. [96, 97] note two major iNKT subtypes: CD4+ and CD4-CD8- or double negative (DN), with CD4+ inducing higher levels of immunoglobulin production. A study by Zeng and colleagues  reports a CD4+CD8α+ subtype: coculturing CD4+CD8α+ iNKT and DN iNKT cells with peripheral B cells, they found that IgG, IgM, and IgA were released by B cells in the absence of -GalCer . CD4+ and DN iNKT cells secreted Th1 and Th2 cytokines when cultured with B cells pulsed with -GalCer but at a lower level compared to iNKT cells cultured with dendritic cells . CD4+ cells were also found to induce regulatory B cell expansion, in addition to increasing B cell production of IL-4 and IL-10 . DN iNKT cells were found to express CD107α (a cytotoxic degranulation marker) when exposed to B cells . In the presence of iNKT cells, B cells were unable to stimulate alloreactive conventional T cells . A recent study by Tang et al.  examined the behavior of iNKT cells subsets based on Ly108 expression, which distinguishes iNKT cells that help B cells and secrete IL-21 from iNKT cells that secrete IL-17. Ly10CD4-NK1.1- secreted IL-17, while Ly10CD4+NK1.1- promoted B cell secretion of IgG isotype anti-nuclear antibodies and IL-21 .
The above studies indicate a modulatory role for iNKT cells on B cells, which appears to both stimulate and control (auto)antibody production. This may be due to differing actions by iNKT cells subsets. The identification of these subsets and their functional phenotypes warrants further study.
4. iNKT Cells and MDSC/Treg Regulation
iNKT cells upon antigenic stimulation and the production of Th1 (IFN-γ and TNF-α) and Th2 (IL-4, IL-5, and IL-13) cytokines can also act through additional suppressive cell subsets such as myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) [116–119]. In vivo cytokine neutralization experiments have revealed a prominent role for IL-4, IL-10, and IFN-γ in the iNKT cells-mediated regulation of T cell lineage development such as Th17 . MDSCs are abundant in liver/spleen and express higher levels of chemokine receptors such as CCR2, CX3CR1, and CXCR2 . They also express CD11b and Gr-1 markers  and therefore encompass diverse cell subsets such as immature DCs, immature macrophages, and granulocytes . In tumor-bearing mice, two main MDSC subtypes have been reported: granulocytic (G-MDSC) and monocytic (M-MDSC) . In humans, MDSCs are predominantly characterized by expression of CD14, whereas G-MDSC are mainly CD15+, both being CD33+ HLA-DR− .
MDSCs are proficient in suppressing T cell proliferation and promoting tumor growth . Both MDSC and Treg cells are major components of the hepatic immune suppressive tumor microenvironment (TME) [126, 127]. In tumor-bearing mice, large amounts of myeloid-derived suppressor cells (MDSCs) are recruited into the liver following Con-A-induced hepatitis . MDSCs are essential for immune mediated suppression within the liver, as they electively reduce IFN-γ production from NKT cells through membrane-bound transforming growth factor-β (TGF-β) . The absence of iNKT cells also markedly decreases the total number of intestinal polyps and is associated with a reduced frequency of Tregs cells and lower expression levels of FoxP3 protein and transcript uniquely in the polyps of ApcMin/+ mice, a model for colorectal cancer .
The exact mechanisms that influence the activity and interaction of iNKT cells/MDSCs in vivo remain ill-defined. However, it has been documented that CD1d-restricted NKT cells can enhance MDSC suppressive activity by secreting IL-13 . IL-13 has been reported to mediate its effect via the IL-4R–STAT6 pathway and can induce TGF-β-producing CD11b+ Gr-1+ MDSC . CD11b+ invariant NKT cells have the ability to inhibit T cell proliferation via membrane-bound TGF-β1 . The induction of MDSC via IL-33 has been proposed as an alternative mechanism for α-GalCer-elicited iNKT cells-mediated immunosuppression .
In contrast, De Santo et al. have demonstrated that the absence of invariant NKT (iNKT) cells in mice during Influenza IAV infection resulted in the expansion of MDSCs, which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality . Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The cross-talk between iNKT cells and MDSCs was CD1d- and CD40-dependent . Ko et al. also showed that iNKT cells activated by α-GalCer-loaded CD11b+ Gr-1+ MDSC could convert MDSC into stimulatory APC . Such reprogrammed MDSC upregulated the expression of CD11b, CD11c, and CD86. Hence, iNKT cells can acquire the ability to enhance suppression or convert immunosuppressive MDSCs into immunity-promoting antigen-presenting cells.
MDSCs are also an abundant cell subset during bone marrow cell (BMC) transfer. MDSCs are essential for iNKT cells-mediated Foxp3+ Treg cell expansion in recipient mice of transplantation tolerance . NKT cells act through bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases . The development of melanoma liver metastases was associated with upregulation of IL-10 in the liver and an elevated expression of IL-10 receptor on liver NK cells. Hepatoprotective effect of certain diet molecules such as the enzymatic isolate of soybeans DT56a was also associated with changes in NKT cells and Tregs . iNKT cells are also capable of diminishing adverse autoimmune responses by increasing both total Tregs and follicular Tregs (Tfr) as shown in the cGVHD murine model that recapitulates several aspects of autoimmunity and internal organ fibrosis .
5. iNKT Cells and Autoimmune Liver Disease
Autoimmune liver diseases (AiLD) include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, and primary sclerosing cholangitis (PSC). The aetiopathogeneses of these conditions have not been fully defined but appear to involve genetic, immunological, and environmental factors working in unison [32–43]. It is widely believed that an imbalance of proinflammatory and anti-inflammatory immune responses within the liver plays a large role in the development of AiLD, with an upregulation of proinflammatory immune responses and decreased or defective anti-inflammatory responses.
(Tregs) dysfunction also appears to play a role [139–142]. In AiLD, self-antigens are presented by antigen-presenting cells that directly or indirectly activate innate immune cells resident within the liver, which also include NKT cells [58, 143, 144]. Tissue-resident immune cells in general have a crucial role in local and systemic immune responses. The liver, in particular, can host a significant number of iNKT cells, but the mechanisms that regulate their survival and homeostasis have not been completely elucidated. Hepatocyte-specific expression of IL-15Rα and localized availability of IL-15 are required to maintain the homeostasis of NK and NKT cells in the liver [145, 146]. Within the liver, NKT cells are mostly found in the sinusoids and are able to produce various cytokines (both proinflammatory and anti-inflammatory) . NKT cells are capable of activating other innate and adaptive immune cells resident within the liver and regulate or enhance immune responses [65, 147, 148]. iNKT cells have been shown to activate hepatic stellate cells , and direct hepatocyte killing has been observed by iNKT cells or by NK cells stimulated by iNKT cells [9, 71]. Durante-Mangoni et al.  found low CD1d and iNKT cells but high CD161+CD56+ NKT cells in the healthy human liver, with an upregulation of CD1d on biliary epithelial cells next to portal tract fibrotic areas in patients with chronic HCV. Hepatic type 2 NKT cells produced large amounts of IFN-gamma and less IL-13 and IL-4 . It was suggested that hepatic cells infected with HCV could increase CD1d and process CD1d liver antigens for presentation . Another study reports that iNKT cells tend to localize in peripheral tissues (such as the liver) as opposed to lymphoid tissue and found that iNKT cells stimulate intrahepatic CD8 T cell effector responses to liver antigens .
Liver iNKT cells have also been shown to constitutively express the costimulatory TNF superfamily receptor OX40 . OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the secretion of proinflammatory cytokines that induce liver injury. The OX40/NKT pyroptosis pathway plays a fundamental role in concanavalin A-induced murine hepatitis as well. The poly(ADP-ribose) polymerase (PARP) proteins also induce cell death and inflammation. Chemical inhibition of PARP activity has been shown to be protective against liver injury during Con-A-induced hepatitis, where inflammation and induced hepatocyte death are mainly mediated by the activated iNKT cells lymphocyte population .
The precise role of iNKT cells in the liver during AiLD, specifically whether they are proinflammatory or anti-inflammatory, has not been fully clarified (Figure 1). Most studies are based on animal models and appear to indicate varying roles for iNKT cells in the AiLD (Table 1).
: increased; : decreased.
(- -): absent; NS: not specified; ND: not different from WT.
6. Autoimmune Hepatitis
Most studies regarding iNKT cells in AIH have been based on the murine model of Con-A-induced AIH [11, 12] and/or further genetic modifications of important signaling molecules such as PKCθ  and SOCS1, 3 [16, 17], as well as the carbon tetrachloride (CCl(4)) model of induced acute hepatitis [20, 151]. Kaneko et al.  found that Con-A induces hepatic NKT cells to produce IL-4, which in turn induced an increase in the expression of granzyme B and Fas ligand (FasL), promoting hepatocyte cytotoxicity. Ajuebor et al.  used the Con-A model to study iNKT cells function and found that Con-A activates iNKT cells, resulting in increased IL-4 and decreased IFN-γ production when CCL2/MCP-1 is neutralized. An interesting study by Takeda and colleagues  found that CD1d-deficient mice lack NKT cells and are resistant to Con-A-induced hepatitis. Transfer of NKT cells from wild-type to CD1d-deficient mice rendered them susceptible to Con-A hepatitis, an event not observed if mice were FasL-deficient . Con-A administration resulted in increased FasL expression on the NKT cells surface and increased FasL-mediated cytotoxicity . Similar results were reported by Biburger et al.  who found that -GalCer enhanced TNF-α secretion, which in turn increased FasL expression on NKT cells. That group proposed that FasL on NKT cells interacts with Fas-expressing hepatocytes, inducing hepatocyte cell death, which raises the possibility that natural autoantigens take the place of -GalCer, being presented to NKT cells by CD1d . In another recent study, TPL2, a MAPKKK kinase that has also been acknowledged for its activating role in macrophage cytokine production , was shown to be a crucial signaling factor in iNKT cells and mediator of hepatic inflammation . Genetic ablation of TPL2 ameliorated liver injury induced by Con-A without affecting NKT cells development in the thymus. The receptor-interacting protein kinase 3 (RIPK3) also plays an important role in programmed necrosis and innate inflammatory responses. Very little is known about the involvement of RIPK3 in NKT cell-mediated immune responses, but recent research has indicated that RIPK3 influences NKT cells function via activation of the mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) . PGAM5-mediated programmed necrosis of hepatocytes has been recently documented to be able to drive acute liver injury . PGAM5 was highly expressed in hepatocytes of patients with AIH and in mice with Con-A-induced experimental hepatitis. Deficiency of PGAM5 protected mice from Con-A-induced hepatocellular death and liver injury. Lately, evidence has been provided to support the role of NKT cells as detectors to sense traumatic injury and to modulate the local immune response toward a restitution phase by affecting the local cytokine milieu . Recently, betulin, an immunomodulatory compound extracted from Hedyotis hedyotidea, was shown to be able to ameliorate concanavalin-A-induced autoimmune hepatitis in mice through inhibition of NKT cells- and T cell-derived IFN-γ, TNF-α, and IL-6 cytokine expression . Of interest, transient expression of transgenic IL-12 in murine liver triggered an inflammatory response mimicking human autoimmune hepatitis, where IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury .
7. Primary Biliary Cholangitis
The role of iNKT cells in PBC has not been fully examined. An early study has reported increased frequency of iNKT cells in the livers of PBC patients, with a decreased number in the peripheral blood . Three distinct subpopulations of iNKT cells have been noted in PBC patients so far: CD4-CD8+, CD4-CD8-, and CD4+CD8- . An immunohistochemical study by Harada et al.  demonstrated CD3+CD57+ cells within the portal tracts and parenchyma of PBC patients and controls, with more pronounced presence of these cells within the portal tracts of PBC patients. CD3+CD57+ cells congregated around areas of injured interlobular bile ducts in PBC cases but not in healthy and pathological controls . Improved detection methods have allowed accurate cytokine measurements from liver CD1d-restricted intrahepatic lymphocytes (IHL), revealing the ability to produce IFNγ, as well as variable levels of IL-10, IL-4, and IL-13 ex vivo [158, 159]. In murine models of PBC, iNKT cells appear to exacerbate murine autoimmune cholangitis, fibrosis, and liver injury [24–26, 160]. Infection of mice with N. aromaticivorans induced signature antibodies against microbial PDC-E2 and its mitochondrial counterpart but also triggered chronic T cell-mediated autoimmunity against small bile ducts . Disease induction required NKT cells, which specifically respond to N. aromaticivorans cell wall alpha-glucuronosyl ceramides presented by CD1d molecules . Mice immunized with -GalCer demonstrated profound disease exacerbation with increased CD8+ T cell infiltrates, portal inflammation, granuloma formation, and bile duct damage . Immunized mice also showed increased levels of anti-mitochondrial antibody (AMA) production . That group suggests that iNKT cells contribute to the perpetuation of PBC following an initial loss of tolerance to PDC-E2 and that iNKT cells play a critical role in PBC recurrence following liver transplantation .
8. Primary Sclerosing Cholangitis
Limited data have been obtained regarding the role of iNKT cells in PSC, despite the fact that cholangiocytes express CD1d and present lipid antigens to NKT cells . In one model of ulcerative colitis with cholangitis in CD1 mice given 2.0% dextran sulfate sodium, researchers found decreased IL-4 levels and increased IFN-γ, with increased numbers of CD4+CD8+ cells in the liver but not in the colon. . The same group of researchers analyzed numbers, surface markers, and cytokine production of mononuclear cells in the mouse model of cholangitis, which had also been given -GalCer . There was increased survival and weight gain noted in the -GalCer treated mice, with decreases in IFN-γ release, CD4/CD8 ratio, and NK and NKT cells populations . Those authors suggest that NKT cells treated with -GalCer may promote a reduction in Th1 and an increase in Th2 cytokine activity . Additionally, in NOD.c3c4 mice that spontaneously develop biliary inflammation in extrahepatic and intrahepatic bile ducts, iNKT cells were more abundant and displayed an activated phenotype . Activation or blocking of NKT cells with α-galactosylceramide or anti-CD1d antibody injections, however, did not affect the biliary phenotype of NOD.c3c4 mice.
9. Vitamin D and iNKT Cells Function: A Role in Autoimmune Liver Disease?
As noted by several studies above, iNKT cells activation or suppression may induce an alteration in the cytokine milieu, in a direction that is either proinflammatory or anti-inflammatory, which appears to be disease-dependent. If the immunomodulatory properties of these cells are validated, they could become the target of novel therapeutic interventions. The question remains as to what therapeutic agents may be used in these conditions, if the notion that their immunomodulatory properties are therapeutic holds true. Recent studies have examined the role of vitamin D in immunomodulation , including the development and regulation of iNKT cells [91, 143–146]. Indeed, iNKT cells and CD4/CD8 intraepithelial lymphocytes are developmentally and functionally dependent on sufficient levels of vitamin D . There has been ongoing research into the role of vitamin D and vitamin D deficiency in the development of autoimmune disease [44, 165, 166]. Multiple studies have noted the rising incidence of autoimmune disease with increasing distance from the equator, which has led to speculation that vitamin D deficiency may play a role in immunomodulation. Interestingly, multiple studies have noted vitamin D deficiency as well as vitamin D receptor (VDR) mutations in patients with autoimmune diseases (well reviewed in ), the most notable of which (mutations) are documented in MS [44, 166–169]. A relatively recent review also highlights the potential role the vitamin D deficiency likely plays in the development of AiLD . ApaI polymorphism of the vitamin D receptor has been also recently shown to affect health-related quality of life in patients with primary sclerosing cholangitis . Low vitamin D levels are also found to be common in patients with PBC and correlated with advanced disease, lack of response to UDCA therapy, and autoimmune disease comorbidity . This alluded to the plausible scenario for a significant role for vitamin D as a prognostic marker of the severity of PBC and possibly the severity of other AiLDs. Recent studies have examined the role of vitamin D in immunomodulation , including the development and regulation of iNKT cells [94, 171–174]. Indeed, iNKT cells and CD4/CD8 intraepithelial lymphocytes are developmentally and functionally dependent on sufficient levels of vitamin D .
Animal models found that vitamin D is required in utero for normal iNKT cells development, with subsequent treatment (such as during clinically evident autoimmune disease) having little benefit [94, 174, 176]. The mechanisms underlying this have been well defined in studies examining the development of iNKT cells and the effect of vitamin D deficiency, as well as that of VDR knockout. The development of iNKT cells begins in the thymus, where they arise from conventional CD4+/CD8+ (double positive or DP) T cells . These early TCR-positive iNKT cells are D and CD24+ and undergo rapid expansion at this stage . Yu and Cantorna  found that, in subjects with adequate vitamin D levels, 91% of D iNKT cells go on to become mature CD24- iNKT cells, with most (61%) apoptotic cells being CD24+. In vitamin D deficiency, only 60% go on to become the CD24- mature type, with equal rates of apoptosis between CD44+ and CD24- cells . Further maturation from CD44-NK1.1- to CD44+NK1.1- occurs in thymic precursors, which is then followed by CD44+NK1.1+ iNKT cells development [177, 178]. Interestingly, vitamin D knockout mice harbor iNKT cells blocked at the CD44+NK1.1- stage [94, 173, 174]. These iNKT cells were functionally defective with regard to the amount of cytokine secretion . Cytokine deficiency and low iNKT cells numbers characterize VDR knockout mice, in contrast to vitamin D-deficient mice that only have decreased iNKT cells numbers but preserved IL-4 and IFN-γ producing function . Recently, protective effects of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis in mice have been attributed to the presence of NKT cells .
Although the effects of vitamin D on iNKT cells development have been elucidated, it is not clear as to whether vitamin D deficiency (or VDR knockout) results in a proinflammatory or anti-inflammatory state. In models of asthma and lung inflammation, abnormal iNKT cells number and function due to VDR knockout have been shown to ameliorate the disease [94, 180–183]. VDR knockout mice are unable to generate airway inflammation due to failed iNKT responses, with VDR knockout mice having decreased iNKT cells . Also, Th2 cells in VDR knockout mice (with the C57BL/6 background) produced less IL-4, a reduction also found in iNKT cells (with BALB/c and C57BL/6 backgrounds) . Additionally, iNKT cells were unable to produce IL-5 and IL-13 (BALB/c background), as well as IL-17 (C57BL/6 background) . However, vitamin D deficiency and consequent abnormal iNKT cells numbers have been suggested to contribute to MS development [184–189], as well as hastening the clinical course of EAE . Vitamin D ameliorates EAE, reduces the Th1 and Th17 cell response, and increases the Treg population [190–192]. A study by Torkildsen and colleagues  demonstrated that three patients with vitamin D-dependent rickets went on to develop MS, despite vitamin D supplementation, which adds to the debate on the effectiveness of early (in utero) vitamin D supplementation versus later treatment during clinical disease.
Recent research on vitamin D receptor- (VDR-) dependent signaling suggests that VDR functions to constrain the inflammatory response by targeting the miRNA-155-SOCS1 (suppressor of cytokine signaling 1) axis. The VDR-miRNA-155-SOCS1 pathway was investigated in the context of the autoimmune response associated with PBC. VDR/miRNA-155-modulated SOCS1 expression was decreased in PBC, leading to insufficient negative regulation of cytokine signaling . 1,25-(OH)(2)-vitamin D(3) also prevented activation of hepatic stellate cells in vitro and ameliorated inflammatory liver damage but not fibrosis in the Abcb4(-/-) murine model of inflammation-induced cholestatic liver injury, fibrosis, and cancer .
The role of iNKT cells in autoimmune disease appears to be multifaceted, with these cells being involved not only in shaping the cytokine environment to be either Th1 or Th2 predominant but also in influencing B cell function and autoantibody production. Whether iNKT cells exert a proinflammatory or anti-inflammatory function varies between autoimmune diseases. The role of iNKT cells in AiLD remains to be elucidated. With the characterization of the functional phenotype of iNKT cells in AiLD and their relationship with disease activity, researchers may be able to establish immunomodulatory therapies to reduce the severity of disease or halt its progression. The immunomodulatory role of vitamin D is intriguing and appears to be highly relevant in this context, further underlying the need for more research.
|AiLD:||Autoimmune liver disease|
|Bregs:||Regulatory B cells|
|EAE:||Experimental autoimmune encephalitis|
|iNKT:||Invariant natural killer T cells|
|NK:||Natural killer cells|
|NKT:||Natural killer T cells|
|PBC:||Primary biliary cholangitis|
|PSC:||Primary sclerosing cholangitis|
|SLE:||Systemic lupus erythematosus|
|TCR:||T cell receptor|
|VDR:||Vitamin D receptor.|
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Daniel S. Smyk and Athanasios Mavropoulos have written a significant part of the first manuscript. Giorgina Mieli-Vergani, Diego Vergani, Marco Lenzi, and Dimitrios P. Bogdanos have critically revised the manuscript and scripted new parts of it. Dimitrios P. Bogdanos had the original idea and produced the final version of the manuscript. All authors have read and approved the final version of the manuscript.
Dr. Daniel S. Smyk was a recipient of an Entry Level Fellowship entitled “the Role of Vitamin D as an Immunomodulator for Invariant NKT-Mediated Regulation in Patients with Primary Biliary Cirrhosis” granted from the European Association for the Study of Liver (EASL).
- C. M. Crosby and M. Kronenberg, “Invariant natural killer T cells: front line fighters in the war against pathogenic microbes,” Immunogenetics, vol. 68, no. 8, pp. 639–648, 2016.
- S. Dasgupta and V. Kumar, “Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset,” Immunogenetics, vol. 68, no. 8, pp. 665–676, 2016.
- M. V. Dhodapkar and V. Kumar, “Type II NKT cells and their emerging role in health and disease,” The Journal of Immunology, vol. 198, no. 3, pp. 1015–1021, 2017.
- S. P. Berzins and D. S. Ritchie, “Natural killer T cells: drivers or passengers in preventing human disease?” Nature Reviews Immunology, vol. 14, no. 9, pp. 640–646, 2014.
- E. Bianchini, S. De Biasi, A. M. Simone et al., “Invariant natural killer T cells and mucosal-associated invariant T cells in multiple sclerosis,” Immunology Letters, vol. 183, pp. 1–7, 2017.
- D. G. Doherty, “Immunity, tolerance and autoimmunity in the liver: A comprehensive review,” Journal of Autoimmunity, vol. 66, pp. 60–75, 2016.
- S. Ferri, M. S. Longhi, C. de Molo et al., “A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis,” Hepatology, vol. 52, no. 3, pp. 999–1007, 2010.
- H. Kita, O. V. Naidenko, M. Kronenberg et al., “Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer,” Gastroenterology, vol. 123, no. 4, pp. 1031–1043, 2002.
- V. Kumar, “NKT-cell subsets: promoters and protectors in inflammatory liver disease,” Journal of Hepatology, vol. 59, no. 3, pp. 618–620, 2013.
- J. Mattner, “Natural killer T (NKT) cells in autoimmune hepatitis,” Current Opinion in Immunology, vol. 25, no. 6, pp. 697–703, 2013.
- S. Toyabe, S. Seki, T. Iiai et al., “Requirement of IL-4 and liver NK1+ T cells for concanavalin A-induced hepatic injury in mice,” Journal of Immunology, vol. 159, no. 3, pp. 1537–1542, 1997.
- G. Tiegs, J. Hentschel, and A. Wendel, “A T cell-dependent experimental liver injury in mice inducible by concanavalin A,” The Journal of Clinical Investigation, vol. 90, no. 1, pp. 196–203, 1992.
- Y. Kaneko, M. Harada, T. Kawano et al., “Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis,” The Journal of Experimental Medicine, vol. 191, no. 1, pp. 105–114, 2000.
- M. N. Ajuebor, C. M. Hogaboam, T. Le, and M. G. Swain, “C-C chemokine ligand 2/monocyte chemoattractant protein-1 directly inhibits NKT cell IL-4 production and is hepatoprotective in T cell-mediated hepatitis in the mouse,” The Journal of Immunology, vol. 170, no. 10, pp. 5252–5259, 2003.
- K. Takeda, Y. Hayakawa, L. van Kaer, H. Matsuda, H. Yagita, and K. Okumura, “Critical contribution of liver natural killer T cells to a murine model of hepatitis,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 97, no. 10, pp. 5498–5503, 2000.
- T. Torisu, M. Nakaya, S. Watanabe et al., “Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis,” Hepatology, vol. 47, no. 5, pp. 1644–1654, 2008.
- M. Nakaya, M. Hashimoto, R. Nakagawa et al., “SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis,” The Journal of Immunology, vol. 183, no. 11, pp. 7047–7053, 2009.
- X. Fang, R. Wang, J. Ma, Y. Ding, W. Shang, and Z. Sun, “Ameliorated ConA-induced hepatitis in the absence of PKC-theta,” PLoS ONE, vol. 7, no. 2, Article ID e31174, 2012.
- A. Filliol, C. Piquet-Pellorce, S. Dion et al., “PARP2 deficiency affects invariant-NKT-cell maturation and protects mice from concanavalin A-induced liver injury,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 313, no. 5, pp. G399–G409, 2017.
- M. I. Arshad, M. Rauch, A. L'Helgoualc'h et al., “NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis,” European Journal of Immunology, vol. 41, no. 8, pp. 2341–2348, 2011.
- D. Vyrla, G. Nikolaidis, F. Oakley et al., “TPL2 kinase is a crucial signaling factor and mediator of NKT effector cytokine expression in immune-mediated liver injury,” The Journal of Immunology, vol. 196, no. 10, pp. 4298–4310, 2016.
- G.-W. He, C. Günther, A. E. Kremer et al., “PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury,” Gut, vol. 66, no. 4, pp. 716–723, 2017.
- Y. J. Kang, B. R. Bang, K. H. Han et al., “Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling,” Nature Communications, vol. 6, article 8371, 2015.
- Y. H. Chuang, Z. X. Lian, G. X. Yang et al., “Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis,” Hepatology, vol. 47, no. 2, pp. 571–580, 2008.
- S.-J. Wu, Y.-H. Yang, K. Tsuneyama et al., “Innate immunity and primary biliary cirrhosis: Activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis,” Hepatology, vol. 53, no. 3, pp. 915–925, 2011.
- C.-H. Chang, Y.-C. Chen, Y.-H. Yu et al., “Innate immunity drives xenobiotic-induced murine autoimmune cholangitis,” Clinical & Experimental Immunology, vol. 177, no. 2, pp. 373–380, 2014.
- E. Schrumpf, X. Jiang, S. Zeissig et al., “The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation,” Physiological Reports, vol. 5, no. 4, Article ID e13117, 2017.
- D. Vergani, M. S. Longhi, D. P. Bogdanos, Y. Ma, and G. Mieli-Vergani, “Autoimmune hepatitis,” Seminars in Immunopathology, vol. 31, no. 3, pp. 421–435, 2009.
- Y. Ma, D. P. Bogdanos, M. J. Hussain et al., “Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2,” Gastroenterology, vol. 130, no. 3, pp. 868–882, 2006.
- D. Vergani and G. Mieli-Vergani, “Aetiopathogenesis of autoimmune hepatitis,” World Journal of Gastroenterology, vol. 14, no. 21, pp. 3306–3312, 2008.
- A. Parés, N. Guañabens, L. Alvarez et al., “Collagen type Iα1 and vitamin D receptor gene polymorphisms and bone mass in primary biliary cirrhosis,” Hepatology, vol. 33, no. 3, pp. 554–560, 2001.
- D. Smyk, E. I. Rigopoulou, H. Baum, A. K. Burroughs, D. Vergani, and D. P. Bogdanos, “Autoimmunity and environment: Am i at risk?” Clinical Reviews in Allergy & Immunology, vol. 42, no. 2, pp. 199–212, 2012.
- D. S. Smyk, E. I. Rigopoulou, and D. P. Bogdanos, “Potential roles for infectious agents in the pathophysiology of primary biliary cirrhosis: What's new?” Current Infectious Disease Reports, vol. 15, no. 1, pp. 14–24, 2013.
- D. S. Smyk, D. P. Bogdanos, M. G. Mytilinaiou, A. K. Burroughs, and E. I. Rigopoulou, “Rheumatoid Arthritis and primary biliary cirrhosis: cause, consequence, or coincidence?” Arthritis & Rheumatology, vol. 2012, Article ID 391567, 7 pages, 2012.
- D. Smyk, E. I. Rigopoulou, Y. Zen et al., “Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis?” World Journal of Gastroenterology, vol. 18, no. 35, pp. 4855–4865, 2012.
- D. S. Smyk, E. I. Rigopoulou, A. Pares et al., “Familial primary biliary cirrhosis: like mother, like daughter?” Acta Gastro-Enterologica Belgica, vol. 75, no. 2, pp. 203–209, 2012.
- C. Rigamonti, D. P. Bogdanos, M. G. Mytilinaiou, D. S. Smyk, E. I. Rigopoulou, and A. K. Burroughs, “Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges,” International Journal of Rheumatology, vol. 2011, Article ID 976427, 12 pages, 2011.
- D. S. Smyk, E. I. Rigopoulou, L. Muratori et al., “Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis,” Annals of Hepatology, vol. 11, no. 1, pp. 7–14, 2012.
- D. S. Smyk, E. I. Rigopoulou, A. Lleo et al., “Immunopathogenesis of primary biliary cirrhosis: an old wives' tale,” Immunity & Ageing, vol. 8, no. 1, article 12, 2011.
- D. Smyk, E. Cholongitas, S. Kriese, E. I. Rigopoulou, and D. P. Bogdanos, “Primary biliary cirrhosis: family stories,” Autoimmune Diseases, vol. 2011, Article ID 189585, 11 pages, 2011.
- D. P. Bogdanos, D. S. Smyk, P. Invernizzi et al., “Infectome: A platform to trace infectious triggers of autoimmunity,” Autoimmunity Reviews, vol. 12, no. 7, pp. 726–740, 2013.
- D. P. Bogdanos, D. S. Smyk, P. Invernizzi et al., “Tracing environmental markers of autoimmunity: Introducing the infectome,” Immunologic Research, vol. 56, no. 2-3, pp. 220–240, 2013.
- D. P. Bogdanos, D. S. Smyk, E. I. Rigopoulou et al., “Twin studies in autoimmune disease: Genetics, gender and environment,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. J156–J169, 2012.
- D. S. Smyk, T. Orfanidou, P. Invernizzi, D. P. Bogdanos, and M. Lenzi, “Vitamin D in autoimmune liver disease,” Clinics and Research in Hepatology and Gastroenterology, vol. 37, no. 5, pp. 535–545, 2013.
- N. Agmon-Levin, R. Kopilov, C. Selmi et al., “Vitamin D in primary biliary cirrhosis, a plausible marker of advanced disease,” Immunologic Research, vol. 61, no. 1-2, pp. 141–146, 2015.
- C. Efe, T. Kav, C. Aydin et al., “Low serum vitamin D levels are associated with severe histological features and poor response to therapy in patients with autoimmune hepatitis,” Digestive Diseases and Sciences, vol. 59, no. 12, pp. 3035–3042, 2014.
- A. Bendelac, P. B. Savage, and L. Teyton, “The biology of NKT cells,” Annual Review of Immunology, vol. 25, pp. 297–336, 2007.
- M. Brigl and M. B. Brenner, “CD1: antigen presentation and T cell function,” Annual Review of Immunology, vol. 22, pp. 817–890, 2004.
- M. Taniguchi, M. Harada, S. Kojo et al., “The regulatory role of Valpha14 NKT cells in innate and acquired immune response,” Annual Review of Immunology, vol. 21, pp. 483–513, 2003.
- M. Alpa, B. Ferrero, R. Cavallo et al., “Anti-neuronal antibodies in patients with HCV-related mixed cryoglobulinemia,” Autoimmunity Reviews, vol. 8, no. 1, pp. 56–58, 2008.
- E. Girardi, I. Maricic, J. Wang et al., “Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens,” Nature Immunology, vol. 13, no. 9, pp. 851–856, 2012.
- P. Lan, Y. Fan, Y. Zhao et al., “TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury,” The Journal of Clinical Investigation, vol. 127, no. 6, pp. 2222–2234, 2017.
- A. Barbarin, E. Cayssials, F. Jacomet et al., “Phenotype of NK-Like CD8(+) T cells with innate features in humans and their relevance in cancer diseases,” Frontiers in Immunology, vol. 8, article 316, 2017.
- R. R. Kulkarni, A. I. Villanueva, L. R. Read et al., “CpG oligonucleotide-mediated co-stimulation of mouse invariant natural killer T cells negatively regulates their activation status,” Cell and Tissue Research, vol. 369, no. 3, pp. 541–554, 2017.
- R. R. Brutkiewicz, “CD1d ligands: The good, the bad, and the ugly,” The Journal of Immunology, vol. 177, no. 2, pp. 769–775, 2006.
- M. Shimamura, Y. Masaki, N. Tatsuya et al., “Activation of invariant natural killer T cells stimulated with microbial alpha-mannosyl glycolipids,” Scientific Reports, vol. 7, no. 1, article 9703, 2017.
- J. Mattner, K. L. DeBord, N. Ismail et al., “Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections,” Nature, vol. 434, no. 7032, pp. 525–529, 2005.
- M. G. Swain, “Natural killer T cells within the liver: Conductors of the hepatic immune orchestra,” Digestive Diseases, vol. 28, no. 1, pp. 7–13, 2010.
- L. Van Kaer, V. V. Parekh, and L. Wu, “Invariant NK T cells: Potential for immunotherapeutic targeting with glycolipid antigens,” Immunotherapy, vol. 3, no. 1, pp. 59–75, 2011.
- L. Van Kaer, V. V. Parekh, and L. Wu, “Invariant natural killer T cells: Bridging innate and adaptive immunity,” Cell and Tissue Research, vol. 343, no. 1, pp. 43–55, 2011.
- T. L. Osmond, K. J. Farrand, G. F. Painter, C. Ruedl, T. R. Petersen, and I. F. Hermans, “Activated NKT Cells can condition different splenic dendritic cell subsets to respond more effectively to TLR engagement and enhance cross-priming,” The Journal of Immunology, vol. 195, no. 3, pp. 821–831, 2015.
- M. Brigl, R. V. Tatituri, G. F. Watts et al., “Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection,” The Journal of Experimental Medicine, vol. 208, no. 6, pp. 1163–1177, 2011.
- S. Kumar, H. Ingle, D. V. R. Prasad, and H. Kumar, “Recognition of bacterial infection by innate immune sensors,” Critical Reviews in Microbiology, vol. 39, no. 3, pp. 229–246, 2013.
- S. B. Wilson and T. L. Delovitch, “Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity,” Nature Reviews Immunology, vol. 3, no. 3, pp. 211–222, 2003.
- X. Weng, Y. He, L. Visvabharathy et al., “Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease,” Journal of Hepatology, 2017.
- L. Van Kaer, L. Wu, and V. V. Parekh, “Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis,” The Journal of Immunology, vol. 146, no. 1, pp. 1–10, 2015.
- C. de Andrés, L. Fernández-Paredes, M. Tejera-Alhambra, B. Alonso, R. Ramos-Medina, and S. Sánchez-Ramón, “Activation of blood CD3+CD56+CD8+ T cells during pregnancy and multiple sclerosis,” Frontiers in Immunology, vol. 8, article 196, 2017.
- V. V. Parekh, M. T. Wilson, D. Olivares-Villagómez et al., “Glycolipid antigen induces long-term natural killer T cell anergy in mice,” The Journal of Clinical Investigation, vol. 115, no. 9, pp. 2572–2583, 2005.
- V. V. Parekh, L. Wu, D. Olivares-Villagómez, K. T. Wilson, and L. Van Kaer, “Activated invariant NKT cells control central nervous system autoimmunity in a mechanism that involves myeloid-derived suppressor cells,” The Journal of Immunology, vol. 190, no. 5, pp. 1948–1960, 2013.
- L. V. Kaer, “α-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles,” Nature Reviews Immunology, vol. 5, no. 1, pp. 31–42, 2005.
- V. Kumar and T. L. Delovitch, “Different subsets of natural killer T cells may vary in their roles in health and disease,” The Journal of Immunology, vol. 142, no. 3, pp. 321–336, 2014.
- E. Ambrosino, M. Terabe, R. C. Halder et al., “Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis,” The Journal of Immunology, vol. 179, no. 8, pp. 5126–5136, 2007.
- R. C. Halder, C. Aguilera, I. Maricic, and V. Kumar, “Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease,” The Journal of Clinical Investigation, vol. 117, no. 8, pp. 2302–2312, 2007.
- P. Arrenberg, R. Halder, and V. Kumar, “Cross-regulation between distinct natural killer T cell subsets influences immune response to self and foreign antigens,” Journal of Cellular Physiology, vol. 218, no. 2, pp. 246–250, 2009.
- P. Arrenberg, I. Maricic, and V. Kumar, “Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice,” Gastroenterology, vol. 140, no. 2, pp. 646–655, 2011.
- S. Ishikawa, K. Ikejima, H. Yamagata et al., “CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice,” Journal of Hepatology, vol. 54, no. 6, pp. 1195–1204, 2011.
- W.-K. Syn, K. M. Agboola, M. Swiderska et al., “NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease,” Gut, vol. 61, no. 9, pp. 1323–1329, 2012.
- K. L. Wallace, M. A. Marshall, S. I. Ramos et al., “NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines,” Blood, vol. 114, no. 3, pp. 667–676, 2009.
- D. Simon, E. Kozlowski, and H. Simon, “Natural killer T cells expressing IFN-γ and IL-4 in lesional skin of atopic eczema,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 64, no. 11, pp. 1681–1684, 2009.
- I. J. Fuss, B. Joshi, Z. Yang et al., “IL-13Rα2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis,” Gut, vol. 63, no. 11, pp. 1728–1736, 2014.
- M. S. Duthie, M. Kahn, M. White, R. P. Kapur, and S. J. Kahn, “Critical proinflammatory and anti-inflammatory functions of different subsets of CD1d-restricted natural killer T cells during Trypanosoma cruzi infection,” Infection and Immunity, vol. 73, no. 1, pp. 181–192, 2005.
- T. Mallevaey, J. Fontaine, L. Breuilh et al., “Invariant and noninvariant natural killer T cells exert opposite regulatory functions on the immune response during murine schistosomiasis,” Infection and Immunity, vol. 75, no. 5, pp. 2171–2180, 2007.
- Y. Miyazaki, S. Miyake, A. Chiba, O. Lantz, and T. Yamamura, “Mucosal-associated invariant T cells regulate Th1 response in multiple sclerosis,” International Immunology, vol. 23, no. 9, pp. 529–535, 2011.
- A. Chiba, S. Oki, K. Miyamoto, H. Hashimoto, T. Yamamura, and S. Miyake, “Suppression of collagen-induced arthritis by natural killer T cell activation with OCH, a sphingosine-truncated analog of α-galactosylceramide,” Arthritis & Rheumatology, vol. 50, no. 1, pp. 305–313, 2004.
- A. W. Jahng, I. Maricic, B. Pedersen et al., “Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis,” The Journal of Experimental Medicine, vol. 194, no. 12, pp. 1789–1799, 2001.
- K. Miyamoto, S. Miyake, and T. Yamamura, “A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells,” Nature, vol. 413, no. 6855, pp. 531–534, 2001.
- A. K. Singh, M. T. Wilson, S. Hong et al., “Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis,” The Journal of Experimental Medicine, vol. 194, no. 12, pp. 1801–1811, 2001.
- R. Furlan, A. Bergami, D. Cantarella et al., “Activation of invariant NKT cells by alphaGalCer administration protects mice from MOG35-55-induced EAE: critical roles for administration route and IFN-gamma,” European Journal of Immunology, vol. 33, no. 7, pp. 1830–1838, 2003.
- L. T. Mars, L. Araujo, P. Kerschen et al., “Invariant NKT cells inhibit development of the Th17 lineage,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 106, no. 15, pp. 6238–6243, 2009.
- S. Hong, M. T. Wilson, I. Serizawa et al., “The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice,” Nature Medicine, vol. 7, no. 9, pp. 1052–1056, 2001.
- S. Sharif, G. A. Arreaza, P. Zucker et al., “Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes,” Nature Medicine, vol. 7, no. 9, pp. 1057–1062, 2001.
- M. Godo, T. Sessler, and P. Hamar, “Role of invariant natural killer T (iNKT) cells in systemic lupus erythematosus,” Current Medicinal Chemistry, vol. 15, no. 18, pp. 1778–1787, 2008.
- E. H. Meyer, S. Goya, O. Akbari et al., “Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 103, no. 8, pp. 2782–2787, 2006.
- S. Yu, J. Zhao, and M. T. Cantorna, “Invariant NKT cell defects in vitamin D receptor knockout mice prevents experimental lung inflammation,” The Journal of Immunology, vol. 187, no. 9, pp. 4907–4912, 2011.
- R. A. Campos, M. Szczepanik, A. Itakura et al., “Cutaneous immunization rapidly activates liver invariant Vα14 NKT cells stimulating B-1 B cells to initiate T cell recruitment for elicitation of contact sensitivity,” The Journal of Experimental Medicine, vol. 198, no. 12, pp. 1785–1796, 2003.
- G. Galli, S. Nuti, S. Tavarini et al., “CD1d-restricted help to B cells by human invariant natural killer T lymphocytes,” The Journal of Experimental Medicine, vol. 197, no. 8, pp. 1051–1057, 2003.
- G. Galli, S. Nuti, S. Tavarini et al., “Innate immune responses support adaptive immunity: NKT cells induce B cell activation,” Vaccine, vol. 21, no. 2, pp. S48–S54, 2003.
- F. Wermeling, S. M. Lind, E. D. Jordö, S. L. Cardell, and M. C. I. Karlsson, “Invariant NKT cells limit activation of autoreactive CD1d-positive B cells,” The Journal of Experimental Medicine, vol. 207, no. 5, pp. 943–952, 2010.
- P. Barral, J. Eckl-Dorna, N. E. Harwood et al., “B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 24, pp. 8345–8350, 2008.
- W. Almishri, J. Deans, and M. G. Swain, “Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice,” Journal of Hepatology, vol. 63, no. 4, pp. 943–951, 2015.
- J. Fjelbye, J. C. Antvorskov, K. Buschard, S. Issazadeh-Navikas, and K. Engkilde, “CD1d knockout mice exhibit aggravated contact hypersensitivity responses due to reduced interleukin-10 production predominantly by regulatory B cells,” Experimental Dermatology, vol. 24, no. 11, pp. 853–856, 2015.
- C. Mauri and M. Menon, “Human regulatory B cells in health and disease: Therapeutic potential,” The Journal of Clinical Investigation, vol. 127, no. 3, pp. 772–779, 2017.
- I. Kalampokis, A. Yoshizaki, and T. F. Tedder, “IL-10-producing regulatory B cells (B10 cells) in autoimmune disease,” Arthritis Research & Therapy, vol. 15, supplement 1, article S1, 2013.
- A. Mavropoulos, T. Simopoulou, A. Varna et al., “Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis,” Arthritis & Rheumatology, vol. 68, no. 2, pp. 494–504, 2016.
- A. Mavropoulos, A. Varna, E. Zafiriou et al., “IL-10 producing Bregs are impaired in psoriatic arthritis and psoriasis and inversely correlate with IL-17- and IFNγ-producing T cells,” Clinical Immunology, vol. 184, pp. 33–41, 2017.
- E. Bialecki, C. Paget, J. Fontaine, M. Capron, F. Trottein, and C. Faveeuw, “Role of marginal zone B lymphocytes in invariant NKT cell activation,” The Journal of Immunology, vol. 182, no. 10, pp. 6105–6113, 2009.
- E. Tonti, G. Galli, C. Malzone, S. Abrignani, G. Casorati, and P. Dellabona, “NKT-cell help to B lymphocytes can occur independently of cognate interaction,” Blood, vol. 113, no. 2, pp. 370–376, 2009.
- J.-Q. Yang, X. Wen, P. J. Kim, and R. R. Singh, “Invariant NKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner,” The Journal of Immunology, vol. 186, no. 3, pp. 1512–1520, 2011.
- G. Galli, P. Pittoni, E. Tonti et al., “Invariant NKT cells sustain specific B cell responses and memory,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 104, no. 10, pp. 3984–3989, 2007.
- R. Amanuma, T. Nakajima, H. Yoshie, and K. Yamazaki, “Increased infiltration of CD1d and natural killer T cells in periodontal disease tissues,” Journal of Periodontal Research, vol. 41, no. 1, pp. 73–79, 2006.
- P. W. Askenase, A. Itakura, M. C. Leite-de-Moraes et al., “TLR-dependent IL-4 production by invariant Valpha14+Jalpha18+ NKT cells to initiate contact sensitivity in vivo,” The Journal of Immunology, vol. 175, no. 10, pp. 6390–6401, 2005.
- R. A. Campos, M. Szczepanik, M. Lisbonne, A. Itakura, M. Leite-De-Moraes, and P. W. Askenase, “Invariant NKT cells rapidly activated via immunization with diverse contact antigens collaborate in vitro with B-1 cells to initiate contact sensitivity,” The Journal of Immunology, vol. 177, no. 6, pp. 3686–3694, 2006.
- E. Tonti, M. Fedeli, A. Napolitano et al., “Follicular helper NKT cells induce limited B cell responses and germinal center formation in the absence of CD4(+) T cell help,” The Journal of Immunology, vol. 188, no. 7, pp. 3217–3222, 2012.
- S. G. Zeng, Y. G. Ghnewa, V. P. O'Reilly et al., “Human invariant NKT cell subsets differentially promote differentiation, antibody production, and T cell stimulation by B cells in vitro,” The Journal of Immunology, vol. 191, no. 4, pp. 1666–1676, 2013.
- X. Tang, B. Zhang, J. A. Jarrell et al., “Ly108 expression distinguishes subsets of invariant NKT cells that help autoantibody production and secrete IL-21 from those that secrete IL-17 in lupus prone NZB/W mice,” Journal of Autoimmunity, vol. 50, pp. 87–98, 2014.
- L. Wu and L. Van Kaer, “Natural killer T cells and autoimmune disease,” Current Molecular Medicine, vol. 9, no. 1, pp. 4–14, 2009.
- S. Hegde, L. Fox, X. Wang, and J. E. Gumperz, “Autoreactive natural killer T cells: Promoting immune protection and immune tolerance through varied interactions with myeloid antigen-presenting cells,” The Journal of Immunology, vol. 130, no. 4, pp. 471–483, 2010.
- S. Natarajan and A. W. Thomson, “Tolerogenic dendritic cells and myeloid-derived suppressor cells: Potential for regulation and therapy of liver auto- and alloimmunity,” Immunobiology, vol. 215, no. 9-10, pp. 698–703, 2010.
- V. O'Reilly, S. G. Zeng, G. Bricard et al., “Distinct and overlapping effector functions of expanded human CD4+, cd8α+ and CD4-CD8α- invariant natural killer T cells,” PLoS ONE, vol. 6, no. 12, Article ID e28648, 2011.
- D. Ilkovitch and D. M. Lopez, “The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression,” Cancer Research, vol. 69, no. 13, pp. 5514–5521, 2009.
- D. I. Gabrilovich, V. Bronte, S.-H. Chen et al., “The terminology issue for myeloid-derived suppressor cells,” Cancer Research, vol. 67, no. 1, article 425; author reply 426, 2007.
- A. Wilkerson, J. Kim, A. Y. Huang, and M. Zhang, “Nanoparticle systems modulating myeloid-derived suppressor cells for cancer immunotherapy,” Current Topics in Medicinal Chemistry, vol. 17, no. 16, pp. 1843–1857, 2017.
- M. A. Pegues, I. L. McWilliams, and A. J. Szalai, “C-reactive protein exacerbates renal ischemia-reperfusion injury: Are myeloid-derived suppressor cells to blame?” American Journal of Physiology-Renal Physiology, vol. 311, no. 1, pp. F176–F181, 2016.
- I. Poschke, D. Mougiakakos, J. Hansson, G. V. Masucci, and R. Kiessling, “Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign,” Cancer Research, vol. 70, no. 11, pp. 4335–4345, 2010.
- G. Gallina, L. Dolcetti, P. Serafini et al., “Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells,” The Journal of Clinical Investigation, vol. 116, no. 10, pp. 2777–2790, 2006.
- D. Lindau, P. Gielen, M. Kroesen, P. Wesseling, and G. J. Adema, “The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells,” The Journal of Immunology, vol. 138, no. 2, pp. 105–115, 2013.
- F. Mussai, C. De Santo, and V. Cerundolo, “Interaction between invariant NKT cells and myeloid-derived suppressor cells in cancer patients: Evidence and therapeutic opportunities,” Journal of Immunotherapy, vol. 35, no. 6, pp. 449–459, 2012.
- H. Zhang, Z. Li, L. Wang et al., “Critical role of myeloid-derived suppressor cells in tumor-induced liver immune suppression through inhibition of NKT cell function,” Frontiers in Immunology, vol. 8, article 129, 2017.
- Y. Wang, S. Sedimbi, L. Löfbom, A. K. Singh, S. A. Porcelli, and S. L. Cardell, “Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells,” Mucosal Immunology, vol. 11, no. 1, pp. 131–143, 2018.
- M. Terabe, C. Khanna, S. Bose et al., “CD1d-restricted natural killer T cells can down-regulate tumor immunosurveillance independent of interleukin-4 receptor-signal transducer and activator of transcription 6 or transforming growth factor-β,” Cancer Research, vol. 66, no. 7, pp. 3869–3875, 2006.
- Y. Han, Z. Jiang, Z. Chen et al., “Pathogen-expanded CD11b+ invariant NKT cells feedback inhibit T cell proliferation via membrane-bound TGF-β1,” Journal of Autoimmunity, vol. 58, pp. 21–35, 2015.
- J. Huang, Y. Tsai, Y. Chang et al., “alpha-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3,” The Journal of Immunology, vol. 192, no. 4, pp. 1972–1981, 2014.
- C. De Santo, M. Salio, S. H. Masri et al., “Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans,” The Journal of Clinical Investigation, vol. 118, no. 12, pp. 4036–4048, 2008.
- H.-J. Ko, J.-M. Lee, Y.-J. Kim, Y.-S. Kim, K.-A. Lee, and C.-Y. Kang, “Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: An alternative cell-based antitumor vaccine,” The Journal of Immunology, vol. 182, no. 4, pp. 1818–1828, 2009.
- S. Miyairi, T. Hirai, R. Ishii et al., “Donor bone marrow cells are essential for iNKT cell-mediated Foxp3+ Treg cell expansion in a murine model of transplantation tolerance,” European Journal of Immunology, vol. 47, no. 4, pp. 734–742, 2017.
- L. Sadegh, P. W. Chen, J. R. Brown, Z. Han, and J. Y. Niederkorn, “NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases,” International Journal of Cancer, vol. 137, no. 5, pp. 1085–1094, 2015.
- Y. Shabat, Y. Lichtenstein, L. Zolotarov, A. Ben Ya'acov, and Y. Ilan, “Hepatoprotective effect of DT56a is associated with changes in natural killer T cells and regulatory T cells,” Journal of Digestive Diseases, vol. 14, no. 2, pp. 84–92, 2013.
- J. Du, K. Paz, G. Thangavelu et al., “Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells,” Blood, vol. 129, no. 23, pp. 3121–3125, 2017.
- M. S. Longhi, Y. Ma, G. Mieli-Vergani, and D. Vergani, “Regulatory T cells in autoimmune hepatitis,” Journal of Hepatology, vol. 57, no. 4, pp. 932–933; author reply 933-4, 2012.
- M. S. Longhi, Y. Ma, D. P. Bogdanos, P. Cheeseman, G. Mieli-Vergani, and D. Vergani, “Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease,” Journal of Hepatology, vol. 41, no. 1, pp. 31–37, 2004.
- M. S. Longhi, Y. Ma, R. R. Mitry et al., “Effect of CD4+CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis,” Journal of Autoimmunity, vol. 25, no. 1, pp. 63–71, 2005.
- C. R. Grant, R. Liberal, B. S. Holder et al., “Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis,” Hepatology, vol. 59, no. 3, pp. 1007–1015, 2014.
- T. Santodomingo-Garzon and M. G. Swain, “Role of NKT cells in autoimmune liver disease,” Autoimmunity Reviews, vol. 10, no. 12, pp. 793–800, 2011.
- M. G. Swain, “Hepatic NKT cells: Friend or foe?” Clinical Science, vol. 114, no. 7, pp. 457–466, 2008.
- Y. Cepero-Donates, V. Rakotoarivelo, M. Mayhue, A. Ma, Y.-G. Chen, and S. Ramanathan, “Homeostasis of IL-15 dependent lymphocyte subsets in the liver,” Cytokine, vol. 82, pp. 95–101, 2016.
- L. E. Gordy, J. S. Bezbradica, A. I. Flyak et al., “IL-15 regulates homeostasis and terminal maturation of NKT cells,” The Journal of Immunology, vol. 187, no. 12, pp. 6335–6345, 2011.
- K. Kakimi, L. G. Guidotti, Y. Koezuka, and F. V. Chisari, “Natural killer T cell activation inhibits hepatitis B virus replication in vivo,” The Journal of Experimental Medicine, vol. 192, no. 7, pp. 921–930, 2000.
- Z. Trobonjaca, A. Kroger, D. Stober et al., “Activating immunity in the liver. II. IFN-beta attenuates NK cell-dependent liver injury triggered by liver NKT cell activation,” The Journal of Immunology, vol. 168, no. 8, pp. 3763–3770, 2002.
- E. Durante-Mangoni, R. Wang, A. Shaulov et al., “Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells,” The Journal of Immunology, vol. 173, no. 3, pp. 2159–2166, 2004.
- D. Sprengers, F. C. M. Sillé, K. Derkow et al., “Critical Role for CD1d-Restricted Invariant NKT Cells in Stimulating Intrahepatic CD8 T-Cell Responses to Liver Antigen,” Gastroenterology, vol. 134, no. 7, pp. 2132–2143, 2008.
- S. W. Rocha, M. E. de França, and G. B. Rodrigues, “Diethylcarbamazine reduces chronic inflammation and fibrosis in carbon tetrachloride- (CCl(4)-) induced liver injury in mice,” Mediators of Inflammation, vol. 2014, Article ID 696383, 15 pages, 2014.
- M. Biburger and G. Tiegs, “α-galactosylceramide-induced liver injury in mice is mediated by TNF-α but independent of Kupffer cells,” The Journal of Immunology, vol. 175, no. 3, pp. 1540–1550, 2005.
- C. Sanz-Garcia, L. E. Nagy, M. A. Lasunción, M. Fernandez, and S. Alemany, “Cot/tpl2 participates in the activation of macrophages by adiponectin,” Journal of Leukocyte Biology, vol. 95, no. 6, pp. 917–930, 2014.
- P. X. Liew, W.-Y. Lee, and P. Kubes, “iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury,” Immunity, vol. 47, no. 4, pp. 752.e5–765.e5, 2017.
- Y.-Q. Zhou, X.-F. Weng, R. Dou et al., “Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice,” Acta Pharmacologica Sinica, vol. 38, no. 2, pp. 201–210, 2017.
- I. Gil-Farina, M. Di Scala, E. Salido et al., “Transient expression of transgenic IL-12 in mouse liver triggers unremitting inflammation mimicking human autoimmune hepatitis,” The Journal of Immunology, vol. 197, no. 6, pp. 2145–2156, 2016.
- K. Harada, K. Isse, K. Tsuneyama, H. Ohta, and Y. Nakanuma, “Accumulating CD57+CD3+ natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis,” Liver International, vol. 23, no. 2, pp. 94–100, 2003.
- D. Sag, M. Özkan, M. Kronenberg, and G. Wingender, “Improved detection of cytokines produced by invariant NKT cells,” Scientific Reports, vol. 7, no. 1, article 16607, 2017.
- K. Yanagisawa, S. Yue, H. J. Van Der Vliet et al., “Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C,” Journal of Viral Hepatitis, vol. 20, no. 8, pp. 556–565, 2013.
- C.-H. Chang, Y.-C. Chen, W. Zhang, P. S. C. Leung, M. E. Gershwin, and Y.-H. Chuang, “Innate immunity drives the initiation of a murine model of primary biliary cirrhosis,” PLoS ONE, vol. 10, no. 3, Article ID e0121320, 2015.
- J. Mattner, P. B. Savage, P. Leung et al., “Liver autoimmunity triggered by microbial activation of natural killer T cells,” Cell Host & Microbe, vol. 3, no. 5, pp. 304–315, 2008.
- E. Schrumpf, C. Tan, T. H. Karlsen et al., “The biliary epithelium presents antigens to and activates natural killer T cells,” Hepatology, vol. 62, no. 4, pp. 1249–1259, 2015.
- Y. Numata, S. Tazuma, T. Nishioka, Y. Ueno, and K. Chayama, “Immune response in mouse experimental cholangitis associated with colitis induced by dextran sulfate sodium,” Journal of Gastroenterology and Hepatology, vol. 19, no. 8, pp. 910–915, 2004.
- Y. Numata, S. Tazuma, Y. Ueno, T. Nishioka, H. Hyogo, and K. Chayama, “Therapeutic effect of repeated natural killer T cell stimulation in mouse cholangitis complicated by colitis,” Digestive Diseases and Sciences, vol. 50, no. 10, pp. 1844–1851, 2005.
- N. Agmon-Levin, E. Theodor, R. M. Segal, and Y. Shoenfeld, “Vitamin D in systemic and organ-specific autoimmune diseases,” Clinical Reviews in Allergy & Immunology, vol. 45, no. 2, pp. 256–266, 2013.
- A. Antico, M. Tampoia, R. Tozzoli, and N. Bizzaro, “Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature,” Autoimmunity Reviews, vol. 12, no. 2, pp. 127–136, 2012.
- M. T. Cantorna, “Vitamin D and its role in immunology: Multiple sclerosis, and inflammatory bowel disease,” Progress in Biophysics and Molecular Biology, vol. 92, no. 1, pp. 60–64, 2006.
- S. J. Brown, “The role of vitamin D in multiple sclerosis,” Annals of Pharmacotherapy, vol. 40, no. 6, pp. 1158–1161, 2006.
- L. Handunnetthi and S. V. Ramagopalan, “UV radiation, vitamin D, and multiple sclerosis,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 107, no. 33, article E130; author reply E131, 2010.
- A. Kempinska-Podhorodecka, M. Milkiewicz, D. Jabøonski, P. Milkiewicz, and E. Wunsch, “ApaI polymorphism of Vitamin D receptor affects health-related quality of life in patients with primary sclerosing cholangitis,” PLoS ONE, vol. 12, no. 4, Article ID e0176264, 2017.
- V. Mocanu, T. Oboroceanu, and F. Zugun-Eloae, “Current status in vitamin d and regulatory T cells--immunological implications,” Revista Medico-Chirurgicala a Societatii De Medici Si Naturalisti Din Iasi, vol. 117, no. 4, pp. 965–973, 2013.
- G. Disanto, A. E. Handel, J. M. Morahan, and S. V. Ramagopalan, “Comment on “epigenetic reduction in invariant NKT cells following In utero vitamin D deficiency in mice”,” The Journal of Immunology, vol. 186, no. 7, pp. 3803-3804, 2011.
- S. Yu and M. T. Cantorna, “The vitamin D receptor is required for iNKT cell development,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 105, no. 13, pp. 5207–5212, 2008.
- S. Yu and M. T. Cantorna, “Epigenetic reduction in invariant NKT cells following in utero vitamin D deficiency in mice,” The Journal of Immunology, vol. 186, no. 3, pp. 1384–1390, 2011.
- J. H. Ooi, J. Chen, and M. T. Cantorna, “Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors?” Molecular Aspects of Medicine, vol. 33, no. 1, pp. 77–82, 2012.
- Ø. Torkildsen, P. M. Knappskog, H. I. Nyland, and K.-M. Myhr, “Vitamin D-dependent rickets as a possible risk factor for multiple sclerosis,” Archives of Neurology, vol. 65, no. 6, pp. 809–811, 2008.
- L. Gapin, J. L. Matsuda, C. D. Surh, and M. Kronenberg, “NKT cells derive from double-positive thymocytes that are positively selected by CD1d,” Nature Immunology, vol. 2, no. 10, pp. 971–978, 2001.
- K. Benlagha, T. Kyin, A. Beavis, L. Teyton, and A. Bendelac, “A thymic precursor to the NKT cell lineage,” Science, vol. 296, no. 5567, pp. 553–555, 2002.
- A. Waddell, J. Zhao, and M. T. Cantorna, “NKT cells can help mediate the protective effects of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis in mice,” International Immunology, vol. 27, no. 5, pp. 237–244, 2015.
- O. Akbari, P. Stock, R. H. DeKruyff et al., “Role of regulatory T cells in allergy and asthma,” Current Opinion in Immunology, vol. 15, no. 6, pp. 627–633, 2003.
- O. Akbari, P. Stock, E. Meyer et al., “Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity,” Nature Medicine, vol. 9, no. 5, pp. 582–588, 2003.
- A. Wittke, A. Chang, M. Froicu et al., “Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation,” Archives of Biochemistry and Biophysics, vol. 460, no. 2, pp. 306–313, 2007.
- S. Yu, D. Bruce, M. Froicu et al., “Failure of T cell homing, reduced CD4/CD8alphaalpha intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20834–20839, 2008.
- M. T. Cantorna, C. E. Hayes, and H. F. Deluca, “1,25-dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 93, no. 15, pp. 7861–7864, 1996.
- M. T. Kampman, T. Wilsgaard, and S. I. Mellgren, “Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle,” Journal of Neurology, vol. 254, no. 4, pp. 471–477, 2007.
- T.-Y. McDowell, S. Amr, W. J. Culpepper et al., “Sun exposure, vitamin D intake and progression to disability among veterans with progressive multiple sclerosis,” Neuroepidemiology, vol. 37, no. 1, pp. 52–57, 2011.
- K. L. Munger, S. M. Zhang, E. O'Reilly et al., “Vitamin D intake and incidence of multiple sclerosis,” Neurology, vol. 62, no. 1, pp. 60–65, 2004.
- C. Sioka, A. P. Kyritsis, and A. Fotopoulos, “Multiple sclerosis, osteoporosis, and vitamin D,” Journal of the Neurological Sciences, vol. 287, no. 1-2, pp. 1–6, 2009.
- I. A. F. van der Mei, A.-L. Ponsonby, T. Dwyer et al., “Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia,” Journal of Neurology, vol. 254, no. 5, pp. 581–590, 2007.
- D. Bruce, S. Yu, J. H. Ooi, and M. T. Cantorna, “Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling,” International Immunology, vol. 23, no. 8, pp. 519–528, 2011.
- M. T. Cantorna, S. Yu, and D. Bruce, “The paradoxical effects of vitamin D on type 1 mediated immunity,” Molecular Aspects of Medicine, vol. 29, no. 6, pp. 369–375, 2008.
- S. Gorman, M. A. Judge, and P. H. Hart, “Immune-modifying properties of topical vitamin D: focus on dendritic cells and T cells,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 121, no. 1-2, pp. 247–249, 2010.
- A. Kempinska-Podhorodecka, M. Milkiewicz, U. Wasik et al., “Decreased expression of vitamin d receptor affects an immune response in primary biliary cholangitis via the vdr-mirna155-socs1 pathway,” International Journal of Molecular Sciences, vol. 18, no. 2, 2017.
- F. P. Reiter, S. Hohenester, J. M. Nagel et al., “1,25-(OH)(2)-vitamin D(3) prevents activation of hepatic stellate cells in vitro and ameliorates inflammatory liver damage but not fibrosis in the Abcb4(-/-) model,” Biochemical and Biophysical Research Communications, vol. 459, no. 2, pp. 227–233, 2015.
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