International Immunology Advance Access first published online on October 25, 2009
This version published online on October 27, 2009
International Immunology, doi:10.1093/intimm/dxp104
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review-article |
The specialized iNKT cell system recognizes glycolipid antigens and bridges the innate and acquired immune systems with potential applications for cancer therapy
Laboratory of Immune Regulation, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Japan
Correspondence to: M. Taniguchi; E-mail: taniguti{at}rcai.riken.jp
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Abstract |
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Top
Abstract
IntroductionInvariant NKT (iNKT) cells bridge innate and acquired immunity and play an important role in both protective and regulatory responses. The nature of the response is dictated by the initial cytokine environment: interaction with IL-10-producing cells induces negative regulatory Th2/regulatory T cell-type iNKT cells, while that with IL-12-producing cells results in pro-inflammatory Th1-type responses. Particularly, in the anti-tumor response, iNKT cells mediate adjuvant activity by their production of IFN-
, which in turn activates both innate and acquired immune systems. Thus, upon activation of iNKT cells, both MHC– and MHC+ tumor cells can be efficiently eliminated. On the basis of these mechanisms, iNKT cell-targeted adjuvant cell therapies have been developed and have shown great promise in initial clinical trials on cancer patients.
Keywords: adjuvant activity, CD1d, 
-galactosylceramide, invariant V14J18, iNKT cell-targeted adjuvant therapy
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Introduction |
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Different from the enormous diversity of conventional T cells, so-called invariant NKT (iNKT) cells are characterized by a highly restricted repertoire due to their expression of a single invariant TCR
chain, consisting of V14J18 in mice (1) and V24J18 in humans (2, 3), associated with a highly restricted set of Vβ chains. In addition, the limited repertoire of iNKT cells appears to be autoreactive, and thus, iNKT cells may be constantly activated by endogenous glycolipid ligands presented by the monomorphic MHC-like class Ib molecule, CD1d (4, 5). The iNKT cells have the potential to quickly release both Th1 and Th2 cytokines after receiving second signals and can mediate both negative regulatory Th2/regulatory T cell (Treg)-type and pro-inflammatory Th1-type immune responses (1, 6). Therefore, iNKT cells are a glycolipid-specific, CD1d-restricted recognition system that, by virtue of the cytokines produced, can bridge innate and acquired immunity (7). Thus, the discovery of the iNKT cell system has provided new insights into the immune system. Here, we describe the discovery and characterization of iNKT cells, their ligand recognition and how the environment in which they are activated can alter their function. This leads to features that are now being manipulated therapeutically to treat human cancer.
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Discovery of iNKT cells |
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Three independent lines of investigation contributed to the identification of iNKT cells as a novel cell type.
Firstly, in 1986, we identified an invariant V14-containing TCR gene from a suppressor T cell hybridoma, which was utilized by most (12 of 13) of the independently established hybridomas (8). V14 complementary DNAs (cDNAs) isolated from these 12 hybridomas could be categorized into four groups; all of them derived from recombination between the V14 and J18 gene segments with a one-nucleotide N-region (8, 9). As the N-region in all these V–J rearrangements provided the third base of a glycine codon, any nucleotide addition encoded an invariant V14 TCR at the amino acid level. Using an RNase protection assay with an invariant V14 anti-sense probe, V14+ cells were estimated to constitute 1–3% of T cells in spleen, 10–20% in liver, 40% in bone marrow (BM) and 0.4% in the thymus of unmanipulated mice (10, 11).
There are approximately 100 V gene segments and the diversity of the TCR repertoire is calculated to be roughly 108. Thus, the frequency of cells expressing any one particular TCR is expected to be 
1 in 106. On the basis of this estimation, the frequency of cells expressing the invariant V14 TCR in unprimed mice is >104 times higher than expected, which prompted us to consider this a unique population that we termed V14+ cells (10).
Interestingly, all inbred laboratory mouse strains of different MHC haplotypes possessed considerable numbers of V14+ cells, although the numbers of V14+ cells were greatly reduced in β2-microglobulin-deficient mice (12). Since the invariant V14 TCR expression was independent of MHC haplotype or of antigen priming, this led to the idea that V14+ cells were likely to be autoreactive and selected by monomorphic rather than the polymorphic MHC. Moreover, V14+ cells were selected by BM-derived cells, including thymocytes, but not by thymic epithelial cells, as demonstrated by BM chimera experiments (5, 12), suggesting that the selection processes for V14+ cells were unique and distinct from those for conventional T cells. An important finding was that the invariant V14 TCR was used only by iNKT cells but not by conventional T cells since only iNKT cells developed when pre-rearranged V14Vβ8.2 genes were introduced into recombination activating gene-deficient mice (13).
A second line of evidence, reported in 1987 by Fowlkes et al. (14) and Budd et al. (15), was that a small population of CD4–CD8– double-negative (DN) thymocytes exclusively expressed TCR Vβ8, suggesting a unique population with a restricted TCR Vβ8 usage. These cells were later found to express CD44 and NK1.1 (16–18) and to produce both Th1 and Th2 cytokines (19).
The third clue, which provided a link between the above studies, was provided by Lantz and Bendelac (2) in 1994. They established hybridomas from Vβ8+ CD44+ thymocytes and found that they all expressed the invariant V14 TCR messenger RNA (mRNA), strongly suggesting that V14+ cells, Vβ8+ DN thymocytes, and these Vβ8+ CD44+ hybridomas represent the same cell type. Thus, this population was designated as V14 NKT cells (in the mouse) or iNKT cells.
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Ligand recognition by iNKT cells |
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Another important finding of Bendelac et al. (4, 5) was that their hybridomas all recognized CD1d, indicating that the mode of antigen recognition by NKT cells is entirely distinct from that of conventional T cells, which recognize polymorphic MHC.
In 1997, we identified -galactosylceraminde (-GalCer) as a glycolipid ligand for iNKT cells that is presented by CD1d (20). Collectively, the discovery of the glycolipid-specific, CD1d-dependent iNKT cells defined a novel arm of the immune system, distinct from the conventional T cell immune system that mainly recognizes peptides in conjunction with polymorphic MHC molecules.
In 2007, the crystal structure of a complex consisting of -GalCer with human CD1d and human-invariant V24Vβ11 was reported (21). Interestingly, according to their observations, four amino acids (Asp94, Arg95, Gly96 and Ser97) at the beginning of the J18 region of the invariant V24J18 TCR were found to be important for binding with -GalCer and CD1d: Asp94 in J18 (J18–Asp94) interacts with Arg79 on CD1d (CD1d–Arg79); J18–Arg95 interacts with three amino acids on CD1d (CD1d–Ser76, CD1d–Arg79 and CD1d–Asp80) and also with the 3-OH on sphingosine of -GalCer; J18–Gly96 interacts with the 2-OH on galactose of -GalCer and J18-Ser97 interacts with CD1d-Glu150.
Thus, the iNKT TCR chain is responsible for the binding with both CD1d and its ligand. On the other hand, the TCRβ chain does not contribute to -GalCer binding, although Tyr48, Tyr50 and Glu57 on TCRβ, a possible germ line-encoded sequence (22), are responsible for binding with CD1d at Glu83 and Lys86 (23, 24).
The CD1d amino acids Ser76, Arg79, Asp80, Glu83 and Gln150, which are important for binding with either -GalCer or the iNKT TCR (25), are well conserved among species, including mouse, rat and human. Similarly, mouse V14J18 and human V24J18 are highly conserved, so that -GalCer can be used as an iNKT ligand in both species. Moreover, iNKT cells act across species barriers, such that human iNKT cells are fully activated by mouse dendritic cells (DCs), and human DCs can activate mouse iNKT cells (26). Therefore, as the iNKT cell system is identical at least in human and mouse, the mechanisms of iNKT cell-mediated function derived from experiments in mice can be applied to humans. The monomorphic nature of CD1d among different species and the conserved sequences of CD1d and the invariant TCR on iNKT cells also allow -GalCer to be used as a drug for clinical applications (27–29).
Although -GalCer is an exogenous iNKT cell ligand, the existence of endogenous self-ligands has been speculated on the basis of the observation that iNKT cells appear to be activated in vivo; freshly isolated iNKT cells express the IL-12R and activation markers, such as CD69 and CD44 (30). This idea is further supported by the finding that no iNKT cells developed in J18-deficient mice (13), suggesting that the invariant V14J18 chain that is used to form the iNKT cell TCR is also important for recognition of endogenous ligands during thymic development, as well as exogenous ligands such as -GalCer. Similarly, no iNKT cells developed in the absence of CD1d; iNKT cells recognizing self-ligands presented on CD1d are considered to be positively selected during their development (31–33).
Zhou et al. (34) have reported that the glycosphingolipid isoglobotrihexosylceramide (iGb3) is an endogenous ligand for iNKT cells, on the basis of their finding that iNKT cell development was blocked in mice deficient in β-hexosaminidase B, an enzyme involved in iGb3 synthesis. However, iGb3 is only expressed in spinal cord but not in the thymus (35). Moreover, iGb3 synthase-deficient mice have normal iNKT cell function (36). Thus, iGb3 is not the selecting ligand for iNKT cells and the identity of the necessary self-antigens remains an unsolved mystery.
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Second signals that determine iNKT cell function |
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Because of their self-reactivity and ability to quickly release large amounts of cytokines, iNKT cells link the two arms of the immune system, serving as a bridge between innate and acquired immunity. Their recognition of self-ligands does not elicit any iNKT cell effector functions. However, it appears to prime the cells, as manifest by up-regulation of activation markers and accumulation of cytokine mRNAs (37), for the ensuing rapid response to exogenous antigens. This in vivo phenotype of iNKT cells indicates that in the steady state the cells are ready to mediate their functions but require additional signals.
The second signals are the key events that determine iNKT cell functions (Fig. 1A). DCs in the steady state are immature, able to capture antigens but unable to activate conventional T cells. However, iNKT cells can be activated by immature DCs and then reciprocally induce maturation of the DCs. A single injection of free -GalCer in vivo induces a burst of IL-12 production (at 6 h) by DCs followed by IFN- production by iNKT cells (at 16–24 h) (38–43). This response is due to up-regulation of co-stimulatory molecules (CD40) on DCs and CD40 ligand (CD40L) expression on iNKT cells, which are detectable within 2–6 h after -GalCer injection (44). The iNKT cells are necessary for this DC maturation because it does not occur in J18-deficient mice. The iNKT cells together with IL-12 from mature DCs mediate strong adjuvant effects on innate and acquired immunity through the production of IFN- by iNKT cells (45).
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In contrast to the IL-12-initiated iNKT cell-mediated protective function, iNKT cells can also become regulatory-type cells producing IL-10, but not IFN-
, when the cells interact with marginal zone B220+cells or regulatory DCs (DCreg), both of which mainly produce IL-10 but not IL-12 (46) (Fig. 1B). In other words, in the absence of IL-12 signaling, IL-10 converts the bipotential (IL-10 and IFN-) iNKT cell into a unipotential cell with regulatory function, producing IL-10 but not IFN-. These regulatory iNKT cells then induce naive DCs to become DCreg characterized by their production of IL-10, which in turn induces antigen-specific Tr-1-type regulatory CD4+ T cells (Treg) producing IL-10 in the presence of antigen, thereby suppressing antigen-specific immune responses.
In addition to their roles in autoimmunity, transplantation tolerance and tumor immunity, iNKT cells have also anti-pathogen activity with potential to produce IL-17. A RORt+ IL-17-producing iNKT cell subset that lack CD4 and NK1.1 expression is shown to produce large amount of IL-17 upon glycolipid ligand stimulation (47, 48) and involves in the induction of neutrophilia in the airway tissues (47).
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The regulatory function of iNKT cells |
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It is known that iNKT cells can prevent autoimmune disease development and maintain tolerance (49–51). When rat pancreatic islets were transplanted into the livers of mice that had been treated with anti-CD4 to induce tolerance, the mice maintained the xenografts for >100 days (49). The same treatment regimen in J
18-deficient mice did not result in tolerance; however, graft survival was restored when the J18-deficient mice were reconstituted with iNKT cells, suggesting that iNKT cells are essential for maintenance of tolerance (50, 51). The regulatory cascade initiated by regulatory iNKT cells also suppresses development of experimental autoimmune encephalomyelitis (EAE) disease (46) or type I diabetes (52–54).
The function of iNKT cells in EAE (46), diabetes (52, 53) and islet transplantation (55) models can be induced by manipulation of the iNKT cells with repeated -GalCer stimulation. For example, in a non-obese diabetic mouse model in which develops diabetes spontaneously, Th1-type iNKT cells mainly producing IFN- in the local tissues became Th2-type regulatory iNKT cells producing IL-10 but not IFN- after repeated -GalCer injection, resulting in the prevention of diabetes development (52, 53).
Moreover, repeated -GalCer stimulation prevents the rejection of syngeneic islet grafts soon after transplantation and consequently normalizes hyperglycemia in diabetic mice because iNKT cell production of IFN-, which is essential for the initial step in the islet rejection, is inhibited by the repeated -GalCer-mediated stimulation (55).
The mechanism by which repeated -GalCer-mediated stimulation leads to iNKT cell-mediated regulatory function is via the induction of DCreg from naive DCs by iNKT cells (46). IL-10 produced by iNKT cells is responsible for the acquisition of regulatory properties by immature DCs and is characterized by an increase in IL-10 but a reduction in IL-12 production. These cytokine changes in DCs are due to the enhanced phosphorylation of extracellular signal-regulated kinase-1/2 and also to the augmented expression of the nuclear inhibitor of nuclear factor kappaB, I
BNS. The iNKT cell-induced DCreg generate antigen-specific Tr-1-type Tregs, suppressing immune responses.
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By bridging both innate and acquired immunity, iNKT cells mediate adjuvant activity |
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In the initial events of protective responses against pathogens, the activation of DCs is mediated by pattern recognition receptors, such as the Toll-like receptors (56), leading to the production of IL-12. Under physiological conditions, the IL-12R is only detectable on iNKT cells because of their continual weak activation by endogenous ligands, but not on other cell types, such as NK cells or T cells. Therefore, this initially produced IL-12 primarily acts on iNKT cells and enhances their production of IFN-
(57). Thus, the weak responses by iNKT cells stimulated with self-ligands are further augmented by IL-12, indicating that both inherent self-ligand activation and extrinsic IL-12-induced signals are necessary to elicit effective iNKT cell-mediated adjuvant activity, which was first described by Gonzalez-Aseguinolaza et al. (58), followed by the detailed analysis by Fujii et al. (43–45).
IFN- produced by IL-12-activated iNKT cells results in the activation and clonal expansion of CD4+ Th1 cells as well as cytotoxic CD8+ T cells of the acquired immune system, leading to memory or secondary immune responses, and also activates NK cells in the innate immune system. In general, MHC+ target cells are eliminated by the CD8+ T cells, whereas MHC– target cells are killed by NK cells. Since both MHC+ and MHC– cells are present in tumors and, thus, both should be eliminated, iNKT cell-mediated adjuvant activity affecting both innate and acquired immune responses is an important strategy for the treatment of cancer. In fact, the treatment of tumor-bearing mice with -GalCer-pulsed DCs leads to the eradication of established metastatic tumors (59, 60). Thus, the manipulation of DCs to produce IL-12 might be a promising strategy for treatment of cancer to selectively trigger protective anti-tumor immunity through the iNKT cell system.
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Adjuvant therapy using iNKT cell-targeted strategies in patients with advanced lung cancer |
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On the basis of the mechanisms of iNKT cell-mediated adjuvant effects on anti-tumor responses in mice, we predicted that administration of
-GalCer-pulsed DCs would have similar beneficial effects in humans. We have completed a phase I/IIa clinical trial of iNKT cell-mediated adjuvant therapy on a total of 17 patients with advanced lung cancer, including IIIB primary cancer, stage IV and recurrent tumor after surgery. The patients’ own peripheral blood mononuclear cells were pulsed with -GalCer and then administered intravenously. Significant increases in the number of IFN--producing cells detected in 10 out of 17 patients correlated with a prolonged median survival time (MST) of 31.9 months, whereas the patient group with low IFN- production showed their MST of 9.7 month, which is equivalent to the MST of 4.6 month after treatment with chemotherapy. Thus, IFN- may be a good biological marker to predict a favorable clinical course. Although none of these 10 patients (60%) with longer survival time showed tumor regression, those with high IFN- production survived >2 years with only the primary treatment and without tumor progression or metastasis (61).
Although iNKT cell-targeted adjuvant therapy offers a powerful new approach for anti-tumor treatment, we need to establish a combination adjuvant therapy in which antigen-specific CD8+ T cell responses will be more efficiently induced in vivo by using tumor-derived peptides together with -GalCer-loaded DCs.
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Future prospects |
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Since iNKT cells produce both Th1 and Th2 cytokines, it is important to manipulate iNKT cell function in vivo so as to favor the Th2/Treg-type iNKT cells selectively producing IL-10 or Th1-type iNKT cells producing mainly IFN-
. OCH, -GalCer analog with shorter sphingocine, induces Th2-shifted cytokine production and prevents autoimmune disease development. Similarly, a neoglycolipid with an ability to produce shifted IFN- production is also successfully generated. The molecule -carba-GalCer with an -linked carba-galactosyl moiety was produced by replacement of the 5a'-oxygen atom of the pyranose ring of D-galactose of -GalCer with a methylene group. This modification generates an ether bond on the pyranose ring, which is resistant to glycosidase and, thus, more stable than -GalCer in vivo and also creates a new hydrophobic interaction with Pro28 on the invariant V14J18 TCR, resulting in more stable binding. In comparison with -GalCer, -carba-GalCer enhanced production of Th1 cytokines and augmented iNKT cell-mediated adjuvant effects in vivo (62). Therefore, the generation of neoglycolipids may provide optimal therapeutic reagents for protective or regulatory immune responses. |
Funding |
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Grant-in-Aid for Scientific Research, Japan Society for the Promotion of Science (M.T.); Grant-in-Aid for Young Scientists, Japan Society for the Promotion of Science (T.T.).
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Acknowledgements |
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The authors are grateful to Peter Burrows for helpful comments and constructive criticisms in the preparation of the manuscript. We are also grateful to Shin-ichiro Motohashi and Toshinori Nakayama at Chiba University for collaboration on the Phase I/IIa clinical studies.
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Abbreviations |
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| BM, bone marrow |
| CD40L, CD40 ligand |
| cDNA, complementary DNA |
| DC, dendritic cell |
| DCreg, regulatory DCs |
| DN, double negative |
| EAE, experimental autoimmune encephalomyelitis |
| iGb3, isoglobotrihexosylceramide |
| -GalCer, -galactosylceraminde |
| iNKT, invariant NKT |
| mRNA, messenger RNA |
| Treg, regulatory T cells |
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