Invariant Natural Killer T Research Articles

Lymphocytes iNKT et asthme : de la souris à l’homme

The term “Natural Killer T (NKT) cells” was first used in the 1990s to designate T lymphocytes expressing the NK marker NK1.1 (NKR-P1A or CD161). Subsequently, this population turned out to be quite heterogeneous and it is now well-established that it includes several subsets with distinct functional capacities. Among them, the invariant NKT (iNKT) cells are at present the most abundant and best characterized subset. They express the invariant Vα14J αϕ0α18 chain in mice and the Vα14J α18 chain in humans, preferentially paired with limited TCR Vβ chains. This particular T cell population, which recognizes glycolipids instead of peptides, is implicated in the severity of experimental allergic asthma. The influence of iNKT cells in the human pathology is still a matter of discussion. Here, we will briefly address these points in the following paragraphs.

Natural killer T cell and pathophysiology of asthma

Natural killer T (NKT) cell is a special type of T lymphocytes that has both receptor of natural killer (NK) cell (NK1.1, CD161c) and T cell (TCR) and express a conserved or invariant T cell receptor called in mice or Va24 in humans. Invariant NKT (iNKT) cell recognizes lipid antigen presented by CD1d molecules. Marine-sponge-derived glycolipid, -galactosylceremide (-GalCer), binds CD1d at the cell surface of antigen-presenting cells and is presented to iNKT cells. Within hours, iNKT cells become activated and start to secrete Interleukin-4 and interferon-. NKT cell prevents autoimmune diseases, such as type 1 diabetes, experimental allergic encephalomyelitis, systemic lupus erythematous, inflammatory colitis, and Graves' thyroiditis, by activation with -GalCer. In addition, NKT cell is associated with infectious diseases by mycobacteria, leshmania, and virus. Moreover NKT cell is associated with asthma, especially CD4+ iNKT cells. In this review, I will discuss the characteristics of NKT cell and the association with inflammatory diseases, especially asthma.

Deficiency of pulmonary Vα24 Vβ11 natural killer T cells in corticosteroid-naïve sarcoidosis patients

Invariant natural killer T (NKT) cells might contribute to the amplified and prolonged T-cell immune response that characterizes sarcoidosis. Therefore, we want to investigate the frequency and distribution of pulmonary invariant NKT cells in corticosteroid-naïve patients with sarcoidosis. We used multi-parameter flow cytometry with antibodies against CD3, CD4, CD8, CD14, CD19, CD45, CD16/56, TCR Valpha24, and TCR Vbeta11, on bronchoalveolar lavage fluid (BALF), to examine the frequency and distribution of pulmonary invariant NKT cells in 47 newly diagnosed sarcoidosis patients and in 8 control subjects. The frequencies of BALF Valpha24 Vbeta11 invariant NKT cells were significantly lower in patients with sarcoidosis in comparison to control subjects. Moreover, lower invariant NKT cell frequencies in patients with sarcoidosis significantly correlated with exaggerated BALF lymphocytosis and CD4 T cell responses. This study demonstrated a pulmonary deficiency in the frequency of a subset of T cells with immunoregulatory function in patients with sarcoidosis.

Research Highlights: Immunotherapy

Research Highlights: Immunotherapy

β-Glycoglycosphingolipid-Induced Alterations of the STAT Signaling Pathways Are Dependent on CD1d and the Lipid Raft Protein Flotillin-2

Beta-glucosylceramide has been shown to affect natural killer T cell function in models of inflammation. We, therefore, investigated the effects of different beta-glycosphingolipids, including beta-glucosylceramide, on STAT (signal transducers and activators of transcription) signaling pathways and determined whether these effects were mediated by lipid raft microdomains and/or CD1d molecules. The effects of alpha- and beta-structured ligands on the lipid raft protein flotillin-2 were studied in both natural killer T hybridoma cells and leptin-deficient mice. To determine whether CD1d was involved in the effects of the beta-glycosphingolipids, an anti-CD1d blocking antibody was used in a cell proliferation assay system. The downstream effects on the protein phosphorylation levels of STAT1, STAT3, and STAT6 were examined in both immune-mediated hepatitis and hepatoma models. The effects of beta-glycosphingolipids on the STAT signaling pathways were found to be dependent on CD1d. Lipid rafts were affected by both the dose and ratio of the beta-glycosphingolipids and the acyl chain length, and these effects were followed by downstream effects on STAT proteins. Our results show that beta-glycosphingolipids have beneficial effects in natural killer T cell-dependent immune-mediated metabolic and malignant animal models in vivo.

ESCII-PIVAC meeting "Recent advances in cancer immunotherapy with an emphasis on cancer vaccines" held in Athens, 9-11 October 2008.

The conference “Recent advances in cancer immunotherapy with an emphasis on vaccines” was organized by the European Society of Cancer Immunology and Immunotherapy (ESCII) and Progress in Vaccination against Cancer (PIVAC) represented by G. Forni, Turin, Italy; R. Kiessling, Stockholm, Sweden; C. Melief, Leiden, The Netherlands; G. Pawelec, Tubingen, Germany; and M. Papamichail, Athens, Greece. The main aims were to review the state of the art of cancer vaccination using diVerent approaches and the role of various eVector and regulatory immune cells both in animal tumour models and in cancer patients. This report provides a short overview of novel concepts, strategies and clinical developments in the Weld following the Wrst ESCII meeting held also in Athens in 2007. About 150 participants from 17 countries of Europe, Asia, North and South America were attracted by the scientiWc program that consisted of presentations from 37 international experts. Good memories remain not only from the lively discussions of six scientiWc sessions and 40 posters, but also from the beauty of ancient Athens and the social evenings in the down-town with local food and drinks. The Wrst session was opened with a presentation from O. Finn (Pittsburgh, USA) who proposed the concept of abnormal self antigens as a group of tumour associated antigens and emphasized their role in cancer surveillance. Abnormal self antigens (MUC-1 and Cyclin B1 proteins were taken as examples) can also be expressed in nonmalignant situations such as bacterial and viral infections. They induce memory responses and can be a part of the “natural” cancer immune surveillance. Finally, these antigens are immunogenic and safe, and can be used in the vaccination of tumours. C. Baxevanis (Athens, Greece) presented a broad overview of the modern knowledge on the role of CD4 T lymphocytes, as cells orchestrating immune responses in the tumour bearing host. Among them are “eVectors” (Th1 and Th2 cells) and “regulators” [Th17, Natural Killer T (NKT) and regulatory T (Treg) cells]. Interestingly, only Th1 could be considered as strictly promoting and Treg as strictly inhibiting immune responses against tumours, pathogens or self antigens. Thus, Th1 cells play a central role in anti-tumour immunity by mediating direct tumour killing, activating innate mechanisms and improving CTL responses. Th17 cells from TRP-1 TCR transgenic mice can eradicate established B16 melanomas. Several technological improvements have been made to enhance the immunogenicity of MHC class II vaccine approaches. To this end a novel technique has been developed whereby the Ii-Key segment of the immunoregulatory Ii protein is coupled to MHC class II epitopes. The Ii-Key segment catalyzes the binding of the epitope to MHC class II molecules and thereby enhances the potency of the vaccine. While some NKT cells are able to induce immune responses, others can suppress immunity. An importance of invariant NKT cells for tumour immunotherapy was emphasised by V. Cerundolo (Oxford, UK). These cells can be stimulated directly by dendritic cells (DCs) via TLR signalling or indirectly through IL-12 and IL-18. Interestingly, activated invariant NKT cells may abolish immunosuppressive activity of myeloid derived suppressor cells (MDSC) V. Umansky (&) Clinical Cooperation Unit, Dermato-Oncology (G300), German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany e-mail: V.Umansky@dkfz-heidelberg.de

NKT cell immune responses to viral infection

Background: Natural killer T (NKT) cells are a heterogeneous population of innate T cells that have attracted interest because of their potential to regulate immune responses to a variety of pathogens. The most widely studied NKT cell subset is the invariant (i)NKT cells that recognize glycolipids in the context of the CD1d molecule. The multifaceted methods of activation iNKT cells possess and their ability to produce regulatory cytokines has made them a primary target for studies. Objective/methods: To give insights into the roles of iNKT cells during infectious diseases, particularly viral infections. We also highlight mechanisms leading to iNKT cell activation in response to pathogens. Conclusions: iNKT cell's versatility allows them to detect and respond to several viruses. Therapeutic approaches to specifically target iNKT cells will require additional research. Notably, the roles of non-invariant NKT cells in response to pathogens warrant further investigation.

MHC class II‐expressing thymocytes suppress invariant NKT cell development

Natural killer T (NKT) cells are positively selected on cortical thymocytes expressing the non-classical major histocompatibility complex (MHC) class I CD1d molecules. However, it is less clear how NKT cells are negatively selected in the thymus. In this study, we investigated the role of MHC class II expression in NKT cell development. Transgenic mice expressing MHC class II on thymocytes and peripheral T cells had a marked reduction in invariant NKT (iNKT) cells. Reduced numbers of iNKT cells correlated with the absence of in vivo production of cytokines in response to the iNKT cell agonist alpha-galactosylceramide. Using mixed bone marrow chimeras, we found that MHC class II-expressing thymocytes suppressed the development of iNKT cells in trans in a CD4-dependent manner. Our observations have significant implications for human iNKT cell development as human thymocytes express MHC class II, which can lead to an inefficient selection of iNKT cells.

Role of Invariant Natural Killer T (iNKT) Cells in Systemic Lupus Erythematosus

Natural killer T (NKT) cells represent a unique T cell lineage. The NKT cells bearing an invariant TCR (iNKT cells) recognize a small variety of glycolipid antigens in the context of CD1d (non-classical MHC-I) presentation. CD1d-restricted iNKT cells play a regulatory role during an immune response by producing cytokines (IFN-gamma, and IL-4). The identification of alpha-galactosyl-ceramide (alpha-GalCer), a marine sponge derivative as a potent stimulator of iNKT cells has raised the potential of therapeutic iNKT cell activation. Invariant NKT cells have been implicated in several different autoimmune diseases in mice and humans, including systemic lupus erythematosus (SLE). Abnormalities in the number and functions of NKT cells have been observed in SLE patients and mouse strains genetically predisposed to lupus (MRL/lpr, NZB/W F1). Moreover, inverse correlation between the frequency of NKT cells and IgG levels has been observed. Elevated IgG levels in relatives of patients with lupus as well as in patients with lupus were associated with low frequencies of NKT cells. This review focuses on the potential roles of NKT cells in the pathogenesis of SLE. It summarizes recent advances in glycolipid therapy for murine lupus. First, it has been demonstrated, that repeated administration of alpha-GalCer to MRL/lpr mice alleviated inflammatory dermatitis but did not influence kidney disease. Treatment of NZB/W mice with alpha-GalCer resulted in amelioration of SLE symptoms in young mice, but treatment of older animals resulted in disease exacerbation. The effects of NKT cell activation using alpha -GalCer, on disease progression, were influenced by a variety of parameters, including the genetic background of mice, the alpha -GalCer dose, number of injections and the stage of the disease process when treatment was performed. Manipulation of NKT cells in the human system may be a promising treatment alternative for the future, however possible deleterious effects have to be carefully investigated first.

Investigation of the role of CD1d-restricted invariant NKT cells in experimental choroidal neovascularization

Choroidal neovascularization (CNV) is directly related to visual loss in age-related macular degeneration and other macular disorders. We have investigated the role of CD1d-restricted invariant natural killer T (NKT) cells in laser-induced experimental CNV. Quantitative real-time PCR detected increased expression of NKT cell-related genes (Vα14 and CXCL16) in whole eyes undergoing CNV, indicating local accumulation of NKT cells. We found a significant reduction of CNV and lower concentrations of vascular endothelial growth factor (VEGF) in ocular fluid in two different NKT cell-deficient mice, CD1d knockout (KO) and Jα18 KO mice. We also established in vitro co-cultures of retinal pigment epithelial cells and splenic NKT cells, and confirmed NKT cells could produce VEGF in the dish. Moreover, inoculating α-galactosylceramide, the ligand for NKT cells, into the vitreous cavity of C57BL/6 mice promoted CNV. We concluded that NKT cells play an important role in CNV as an inducer of VEGF.

The TNF-Family Receptor DR3 is Essential for Diverse T Cell-Mediated Inflammatory Diseases

DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.

Type I Natural Killer T (iNKT) Cells Regulate Inflammatory Immune Response in Mice Liver Injury Induced by CCl4

Natural killer T (NKT) cells are the predominant lymphocyte population (up to 30 %) in the mouse liver and play an important role in Concanavalin A (Con A) and α‐Galactosylceramide (α‐GalCer) induced liver injury by producing inflammatory cytokines, such as IFN‐γ and TNF‐α and activating other cell populations including NK and T cells. In this study, we examined the role of NKT cells in carbon tetrachloride (CCl4) liver injury using type I, or invariant NKT (iNKT) KO mice (Ja18−/−) and WT C57BL/6 mice. Liver injury in mice was induced by intraperitoneal single injection of 1 ml/kg body weight of 10% CCl4 and samples were collected at different time points. The administration of CCl4 to mice induced liver injury with depletion of NKT cells and elevation of NK cells in the liver in both mice groups. Compared to WT mice, Jα 18−/− mice showed severe liver damage and increased neutrophil infiltration at early time point. Serum levels of inflammatory cytokines, such as TNF‐α, MCP‐1, IL‐4 and IL‐6, as well as mRNA expression were remarkably increased in Jα18−/− mice after CCl4 administration compared to WT mice. These findings suggest that type I NKT cells may protect against inflammatory immune response via suppressing the production of proinflammatory cytokines in early stage liver injury.

Activation of Invariant NKT Cells Exacerbates Experimental Visceral Leishmaniasis

We report that natural killer T (NKT) cells play only a minor physiological role in protection from Leishmania donovani infection in C57BL/6 mice. Furthermore, attempts at therapeutic activation of invariant NKT (iNKT) cells with α-galactosylceramide (α-GalCer) during L. donovani infection exacerbated, rather than ameliorated, experimental visceral leishmaniasis. The inability of α-GalCer to promote anti-parasitic immunity did not result from inefficient antigen presentation caused by infection because α-GalCer–loaded bone marrow–derived dendritic cells were also unable to improve disease resolution. The immune-dampening affect of α-GalCer correlated with a bias towards increased IL-4 production by iNKT cells following α-GalCer stimulation in infected mice compared to naïve controls. However, studies in IL-4–deficient mice, and IL-4 neutralisation in cytokine-sufficient mice revealed that α-GalCer–induced IL-4 production during infection had only a minor role in impaired parasite control. Analysis of liver cell composition following α-GalCer stimulation during an established L. donovani infection revealed important differences, predominantly a decrease in IFNγ+ CD8+ T cells, compared with control-treated mice. Our data clearly illustrate the double-edged sword of NKT cell–based therapy, showing that in some circumstances, such as when sub-clinical or chronic infections exist, iNKT cell activation can have adverse outcomes.

PREVENTION OF INJURY-INDUCED SUPPRESSION OF T-CELL IMMUNITY BY THE Cd1d/NKT CELL-SPECIFIC LIGAND α-GALACTOSYLCERAMIDE

Infection, sepsis, and multiple organ failure continue to be significant factors leading to morbidity and mortality after severe injury. Studies by our laboratory and others have identified injury-induced defects in both innate and adaptive components of host defense. We previously reported that CD1d-restricted natural killer T (NKT) cells actively suppress effector T-cell immunity after burn injury via production of excess IL-4 and failure to produce IFN-gamma. alpha-Galactosylceramide (alpha-GalCer) is a synthetic NKT cell-specific ligand presented exclusively to invariant NKT cells and is known to improve immunity against tumors and infection by promoting IFN-gamma production. Here, we confirmed the role of Valpha14-Jalpha281 invariant NKT cells in mouse model of burn injury-induced suppression of T-cell immunity and further asked whether alpha-GalCer can improve immunity after injury via similar mechanisms. We observed that systemic treatment with alpha-GalCer prevented the injury-induced suppression of Ag-specific T-cell responsiveness both in vitro and in vivo and restored the ability of splenic lymphocytes to produce both IL-2 and IFN-gamma. Moreover, burn injury was associated with diminished expression of major histocompatibility complex II and CD40 on antigen presenting cells that were both restored by alpha-GalCer treatment to levels seen in sham-treated mice. Collectively, these data suggest that, via manipulation of the NKT cell population, we may be able to maintain T-cell function and improve host defense after burn injury.

Antibodies to CD1d enhance thymic expression of invariant NKT TCR and increase the presence of NOD thymic invariant NKT cells

Natural Killer T (NKT) cells can effect both T cell development and peripheral immune responses through T(H)1/T(H)2 cytokines. Some humans with Type 1 Diabetes Mellitus (T1DM) have numerical and functional NKT deficiencies that contribute to disease severity. Correcting these deficiencies inhibits diabetes in the non-obese diabetic (NOD) T1DM model, which shares similar deficiencies. Here we show that antibodies to CD1d, when given during early thymic development, induce specific increases in surface TCR of developing NOD and C57BL/6 CD4(+)CD8(+) (DP) invariant NKT (iNKT) cells. However, the addition of anti-CD1d causes distinct strain-specific population changes in response to treatment. These changes include: (1) a dose-dependent increase in NOD iNKT(TCR)(+) cells and, conversely, (2) an inhibition of B6 iNKT(TCR)(+) cell production. The observed NOD iNKT expansions correlated with diabetes inhibition in an in vitro T1DM system, suggesting that intrathymic anti-CD1d treatment may correct NOD numerical iNKT deficiencies through developmental TCR enhancement.

Protective Role for CD1d-Reactive Invariant Natural Killer T Cells in Cauterization-Induced Corneal Inflammation

Corneal inflammation can be induced by various stimuli, such as chemical burns, trauma, and acute bacterial infection, and directly impairs visual acuity. Natural killer T (NKT) cells belong to a specialized population of leukocytes that coexpress the T-cell receptor and NK markers. This study examined the role of CD1d-reactive invariant NKT cells in cauterization-induced acute corneal inflammation. The corneas of CD1d-knockout (KO) mice and Jalpha18-KO mice (both of which are NKT cell deficient) and control mice were cauterized with silver nitrate. Corneal edema and opacity were examined, and the phenotypes of the corneal-infiltrating cells were analyzed histologically at 24 hours and by flow cytometry at 96 hours. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression of vascular endothelial growth factor (VEGF), interferon (IFN)gamma, and tumor necrosis factor (TNF)alpha in the cauterized corneas. The CD1d-KO and Jalpha18-KO mice had significantly greater levels of corneal edema and opacity than did the control mice. Although the number of infiltrating cells was not significantly different at 96 hours, both groups of NKT cell-deficient mice demonstrated increased early neutrophil accumulation at 24 hours and early expression of VEGF, IFNgamma, and TNFalpha. There was no difference in the level of VEGF-induced corneal neovascularization. NKT cells appear to regulate the early accumulation of neutrophils, protect the cornea from excessive inflammation, and maintain corneal clarity. However, in this study, they did not affect the corneal revascularization process induced by VEGF.

Function and Therapeutic Potential of In Vitro-Expanded Natural Killer T (NKT) Cells from Patients with Hematopoietic Malignancies.

Injection of glycolipid KRN7000 (α-galactosylceramide) into mice induces activation of a specific subpopulation of T cells called invariant NKT (iNKT) cells which are important for tumor cell eradication. NKT cell activation is antigen-specific and dependent on presentation of agonist by the non-polymorphic class I-like molecule CD1d on antigen-presenting cells. In contrast to mouse, injection of KRN7000 into cancer patients did not induce any clinical responses in a published phase I study. This lack of response in part reflects the very low frequency of iNKT (Vα24/Vβ11 T cell receptor) cells in humans and especially in some cancer patients. Therefore, therapies which can increase iNKT cell numbers in patients may enhance the chances of tumor cell killing. Adoptive transfer of in vitro-expanded iNKT cells in combination with KRN7000 may be one therapeutic option. Our group and others have shown that CD1d-positive tumor cell lines are very sensitive to killing by human NKT cells. In contrast, killing of CD1d-negative tumor cells is not directly mediated by NKT cells but can be influenced through cytokines secreted by NKT cells. Based on these results and the reduced frequency of iNKT cells in patients, we hypothesized that NKT cell adoptive therapy could be most beneficial for treatment of patients with CD1d-positive cancers. Previous reports have shown that multiple myeloma (MM), acute myeloid leukemia (AML)-M4, and T-acute lymphoblastic leukemia (ALL) tumor cells express CD1d and may be susceptible to NKT cell killing in vitro. In this proof-of-concept study, we analyzed iNKT cell frequency, expansion, and function from six patients with hematopoietic malignancies (MM and AML). Although the frequency of iNKT cells in patients was extremely low (<0.01% in 5 of 6 patients), in vitro culture of PBMCs with KRN7000 and rhIL-2 induced tremendous NKT cell expansion. After the initial 12–14 day culture, iNKT cells expanded from 300-fold to greater than 2000-fold in 5 of 6 patient samples. Purified iNKT cell lines were generated from 5 of 6 patients and then restimulated every 8–12 days. Within one month, it was possible to obtain more than 100 million NKT cells (4 of 6 donors) from a starting culture of 10 million PBMCs (∼100–6,000 NKT cells). The sorted and expanded iNKT cell lines were then tested for cytokine secretion and cytotoxic activity. Upon activation, patient iNKT cell lines produced relatively normal levels of IFN-γ, IL-4, IL-5, and GM-CSF but slightly reduced amounts of IL-2 and TNFα compared to normal donor iNKT lines. Importantly, patient iNKT cell lines showed potent and dose-dependent killing activity against B, T and monocytic tumor cell lines in a 4h chromium release assay. The cytotoxic activity was both CD1d-restricted and antigen-specific. Near maximal killing of tumor cells was seen at an effector to target cell ratio of 5:1, but killing was seen even at 1:1 (E:T). Three of four patient iNKT cell lines showed strong killing of Jurkat (57–66% killing), MOLT-4 (36–57% killing), CEM (30–46%killing), U-937 (47–49% killing), and CD1d-transfected B cell (54–78% killing) targets at a 5:1 NKT:tumor cell ratio. Based on this data and results of the preliminary toxicology study in non-human primate, we believe that adoptive transfer of expanded iNKT cells plus KRN7000 is safe and may be particularly effective against CD1d-positive tumor cells in vivo.

Innate Vα14+ natural killer T cells mature dendritic cells, leading to strong adaptive immunity

The observation that the glycolipid alpha-galactosylceramide (alpha-GalCer) is a potent stimulator of natural killer T (NKT) cells has provided an important means for investigating NKT cell biology. alpha-GalCer is presented on CD1d to the invariant NKT receptor, leading to interleukin-12 (IL-12) production by dendritic cells (DCs) and to NK cell activation. We review our research on the tumor-protective properties of alpha-GalCer, particularly the major role played by DCs. We compared administration of alpha-GalCer on mature DCs with soluble glycolipid and found that DCs induced more prolonged interferon-gamma (IFN-gamma) production by NKT cells and better protection against B16 melanoma. Human alpha-GalCer-loaded DCs also expanded NKT cell numbers in cancer patients. alpha-GalCer-activated NKT cells were then found to induce DC maturation in vivo. The maturing DCs produced IL-12, upregulated co-stimulatory molecules, and induced adaptive immunity to captured cellular antigens, including prolonged, combined CD4(+)/CD8(+) T-cell immunity to dying tumor cells. Surprisingly, co-stimulator-poor tumor cells, if directly loaded with alpha-GalCer ('tumor/Gal') and injected intravenously, also induced strong NKT- and NK-cell responses. The latter killed the tumor/Gal, which were subsequently cross presented by CD1d on DCs to elicit DC maturation and prolonged adaptive T-cell immunity, which lasted 6-12 months. These findings help explain tumor protection via alpha-GalCer and urge development of the DC-NKT axis to provide innate and adaptive immunity to human cancers.

Role of NKT Cells in the Digestive System. III. Role of NKT cells in intestinal immunity

Natural killer T (NKT) cells are a small subset of unconventional T cells that recognize lipid antigens presented by the nonclassical major histocompatibility complex (MHC) class I molecule CD1d. NKT cells are involved in the host response to a variety of microbial pathogens and likely commensals. In the intestine, invariant and noninvariant NKT cells can be found among intraepithelial lymphocytes and in the lamina propria. Activation of intestinal NKT cells by CD1d-expressing intestinal epithelial cells and professional antigen-presenting cells may contribute to induction of oral tolerance and protection from mucosal infections. On the other hand, sustained and uncontrolled activation of NKT cells may play a pivotal role in the pathogenesis of inflammatory bowel disease. Here we review the current literature on intestinal NKT cells and their function in the intestine in health and disease.

Invariant NKT and NKT-like lymphocytes: Two different T cell subsets that are differentially affected by ageing

The expression on T lymphocytes of surface receptors that are characteristically expressed on NK cells has led to the definition of a T cell subset that has been termed Natural Killer T (NKT) cells. Thus NKT cells constitute a minor lymphocyte population that exhibits features of both T cells and NK cells. However, the term ‘NKT cell’ has been applied variably to cells that express a restricted T-cell receptor (TCR) that recognizes glycolipids (α-GalCer) presented by the MHC-like molecule CD1d and that express CD161, as well as populations of conventional CD8 T cells that show up-regulated expression of NK-cell markers. The CD1d restricted T cells have a semi-invariant TCR using the Vα24Jα18 genes in humans (Vα24Jα18 in mice) and are denominated invariant NKT (iNKT) cells. On the other hand mainstream T cells that express NK associated receptors (NKR) show a highly specialized effector memory phenotype and are frequently referred as NKT-like cells. These T lymphocyte subsets are differentially affected by ageing. Whereas human peripheral blood iNKT cells decrease with age, there is an increase in the percentage of peripheral blood NKT-like T lymphocytes.