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1.  Defective NKT Cell Activation by CD1d+ TRAMP Prostate Tumor Cells Is Corrected by Interleukin-12 with alpha-Galactosylceramide 
PLoS ONE  2010;5(6):e11311.
Numerical and functional defects of invariant natural killer T cells (iNKT) have been documented in human and mouse cancers, resulting in a defect in IFN production in several malignancies. iNKT cells recognize glycolipids presented on CD1d molecules by dendritic and related cells, leading to their activation and thereby regulating immune reactions. Activated iNKT cells cytokine secretion and cytotoxicity can inhibit existing and spontaneous tumor growth, progression, and metastasis. We have identified functional iNKT cell defects in the murine TRAMP prostate cancer model. We found that iNKT cells show the ability to migrate into TRAMP prostate tumors. This infiltration was mediated through CCL2: CCR5 chemokine: receptor interaction. Prostate tumor cells expressing CD1d partially activated iNKT cells, as appreciated by up-regulation of CD25, PD-1 and the IL-12R. However, despite inducing up-regulation of these activation markers and, hence, delivering positive signals, prostate tumor cells inhibited the IL-12-induced STAT4 phosphorylation in a cell-cell contact dependent but CD1d-independent manner. Consequently, tumor cells did not induce secretion of IFNγ by iNKT cells. Blocking the inhibitory Ly49 receptor on iNKT cells in the presence of α-GalCer restored their IFNγ production in vivo and in vitro. However, Ly49 blockade alone was not sufficient. Importantly, this defect could be also be reversed into vigorous secretion of IFNγ by the addition of both IL-12 and the exogenous CD1d ligand alpha-galactosylceramide, but not by IL-12 alone, both in vivo and in vitro. These data underscore the potential to optimize iNKT-based therapeutic approaches.
doi:10.1371/journal.pone.0011311
PMCID: PMC2892484  PMID: 20593019
2.  Therapeutic Targeting the Diverse Immunologic Functions Expressed by Hepatic NKT cells 
Introduction
NKT cells comprise approximately 30% of the hepatic lymphoid population in mice (~50% in humans). Most mouse hepatic NKT cells [invariant (i)NKT cells] express T cell receptors, composed of invariant Vα14Jα18 chains. Unlike conventional T cells, iNKT cells recognize glycolipid molecules presented in association with MHC class Ib (CD1d) molecules. Purportedly, iNKT cells serve a key function in a wide range of immunological events; the precise nature of this function is often unclear. Indeed, the consequences of hepatic iNKT cell activation can be beneficial or detrimental. α-Galactosylceramide, the prototypic glycolipid recognized by the iNKT cell receptor, stimulates the rapid production of both interferon-γ and interleukin-4. The reciprocal suppression exhibited by these cytokines limits the potential therapeutic value of α-galactosylceramide. An extensive research effort is ongoing to develop α-galactosylceramide analogs that modulate iNKT cell activity and selectively promote interferon-γ or interleukin-4.
Areas covered
This review provides a broad overview of hepatic iNKT cells and their purported role in liver disease. Efforts to develop therapeutic agents that promote their beneficial contributions are detailed.
Expert Opinion
While a growing body of literature documents the differential effects of α-GalCer analogs on IFN-γ and IL-4 production, the effects of these analogs on other iNKT cell activities, e.g., cytolysis and the production of other cytokines, remain to be determined. Similarly, an exhaustive examination of the effects of these analogs on inflammation and liver injury in animal models remains prior to considering their utility in clinical trials.
doi:10.1517/14728222.2011.584874
PMCID: PMC3133853  PMID: 21564001
3.  NKT Cell Immune Responses to Viral Infection 
Background
Natural killer T (NKT) cells are a heterogeneous population of innate T cells that have attracted recent 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 therapeutic studies.
Objective/Methods
This review gives insight into the roles of iNKT cells during infectious diseases, particularly viral infections. We also highlight the different mechanisms leading to iNKT cell activation in response to pathogens.
Conclusions
The iNKT cell versatility allows them to detect and respond to several viral infections. However, therapeutic approaches to specifically target iNKT cells will require additional research. Notably, examination of the roles of non-invariant NKT cells in response to pathogens warrant further investigations.
doi:10.1517/14712590802653601
PMCID: PMC2921843  PMID: 19236234
CD1d; Infectious disease; NKT cells; Viruses
4.  Glycolipid ligands of invariant natural killer T cells as vaccine adjuvants 
Expert review of vaccines  2008;7(10):1519-1532.
Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes that recognize glycolipid antigens in the context of the antigen-presenting molecule CD1d. Upon glycolipid antigen stimulation, iNKT cells rapidly produce copious amounts of immunomodulatory cytokines, leading to potent activation of a variety of innate and adaptive immune cells. These immune-potentiating properties of iNKT cells hold great promise for the development of vaccine adjuvants. This review aims to summarize the immunomodulatory activities of iNKT cell ligands and to discuss prospects for developing iNKT cell-based vaccine adjuvants.
doi:10.1586/14760584.7.10.1519
PMCID: PMC2680388  PMID: 19053208
α-galactosylceramide; adjuvant; antigen presentation; CD1d; glycolipid; innate immunity; invariant natural killer T cell
5.  Activated invariant NKT cells control central nervous system autoimmunity in a mechanism that involves myeloid-derived suppressor cells 
Invariant NKT (iNKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the MHC class I-related protein CD1d. Activation of iNKT cells with glycolipid antigens such as the marine sponge-derived reagent α-galactosylceramide (α-GalCer) results in the rapid production of a variety of cytokines and activation of many other immune cell types. These immunomodulatory properties of iNKT cells have been exploited for the development of immunotherapies against a variety of autoimmune and inflammatory diseases but mechanisms by which activated iNKT cells confer disease protection have remained incompletely understood. Here, we demonstrate that glycolipid-activated iNKT cells cooperate with myeloid-derived suppressor cells (MDSCs) in protecting mice against the development of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for multiple sclerosis (MS). We showed that α-GalCer induced the expansion and immunosuppressive activities of MDSCs in the spleen of mice induced for development of EAE. Disease protection in these animals also correlated with recruitment of MDSCs to the central nervous system. Depletion of MDSCs abrogated the protective effects of α-GalCer against EAE and, conversely, adoptive transfer of MDSCs from α-GalCer-treated mice ameliorated passive EAE induced in recipient animals. The cytokines GM-CSF, IL-4 and IFN-γ, produced by activated iNKT cells, and inducible nitric oxide synthase, arginase-1 and IL-10 produced by MDSCs, contributed to these effects. Taken together, our findings have revealed cooperative immunosuppressive interactions between iNKT cells and MDSCs that might be exploited for the development of improved immunotherapies for MS and other autoimmune and inflammatory diseases.
doi:10.4049/jimmunol.1201718
PMCID: PMC3577977  PMID: 23345328
6.  Diacylglycerol Kinase Zeta Positively Controls the Development of iNKT-17 Cells 
PLoS ONE  2013;8(9):e75202.
Invariant natural killer T (iNKT) cells play important roles in bridging innate and adaptive immunity via rapidly producing a variety of cytokines. A small subset of iNKT cells produces IL-17 and is generated in the thymus during iNKT-cell ontogeny. The mechanisms that control the development of these IL-17-producing iNKT-17 cells (iNKT-17) are still not well defined. Diacylglycerol kinase ζ (DGKζ) belongs to a family of enzymes that catalyze the phosphorylation and conversion of diacylglycerol to phosphatidic acid, two important second messengers involved in signaling from numerous receptors. We report here that DGKζ plays an important role in iNKT-17 development. A deficiency of DGKζ in mice causes a significant reduction of iNKT-17 cells, which is correlated with decreased RORγt and IL-23 receptor expression. Interestingly, iNKT-17 defects caused by DGKζ deficiency can be corrected in chimeric mice reconstituted with mixed wild-type and DGKζ-deficient bone marrow cells. Taken together, our data identify DGKζ as an important regulator of iNKT-17 development through iNKT-cell extrinsic mechanisms.
doi:10.1371/journal.pone.0075202
PMCID: PMC3779165  PMID: 24073253
7.  Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178 dependent and is correlated with antigenic potency 
Invariant NKT (iNKT) cells are a unique subset of T lymphocytes that rapidly carry out effector functions following activation with glycolipid Ags, such as the model Ag α-galactosylceramide (αGalCer). Numerous studies have investigated the mechanisms leading to Th1- and Th2 cytokine production by iNKT cells, and the effects of the copious amounts of cytokines these cells produce. Less is known, however, about the mechanisms of iNKT cell cytotoxicity. Here we investigated the effect of antigen availability and strength, as well as the molecules involved in iNKT cytotoxicity. We demonstrate that the iNKT cell cytotoxicity in vivo correlates directly with the amount of CD1d expressed by the targets as well as the TCR affinity for the target glycolipid Ag. iNKT cells from spleen, liver and thymus were comparable in their cytotoxicity in vitro. Surprisingly, we show that the antigen-specific cytotoxicity of iNKT cells in vivo depended almost exclusively on the interaction of CD95 (Fas) with CD178 (FasL), and that this mechanism can be efficiently utilized for tumor protection. Therefore unlike NK cells, which rely mostly on perforin/granzyme mediated mechanisms, the antigen-specific cytotoxicity of iNKT cells in vivo is largely restricted to the CD95/CD178 pathway.
doi:10.4049/jimmunol.1001018
PMCID: PMC2989418  PMID: 20660713
natural killer T cells; T lymphocyte; cytotoxicity; lipid Ags; OCH; C-Gly; CD95/Fas; CD178/FasL
8.  iNKT cell autoreactivity: what is “self” and how is it recognized? 
Nature reviews. Immunology  2010;10(4):272-277.
Following stimulation through their T cell receptor, invariant natural killer T (iNKT) cells act as innate effector cells by rapidly releasing large amounts of effector cytokines and chemokines and therefore have an important role in modulating the ensuing immune response. iNKT cells recognize and are activated by diverse glycolipid antigens, many of which are found in microorganisms. However, iNKT cells also demonstrate some reactivity to “self”. Here, I outline our current understanding of iNKT cell autoreactivity and propose that several self-lipids are probably involved in the positive selection and autoreactivity of iNKT cells.
doi:10.1038/nri2743
PMCID: PMC3070484  PMID: 20224567
9.  Hiding Lipid Presentation: Viral Interference with CD1d-Restricted Invariant Natural Killer T (iNKT) Cell Activation 
Viruses  2012;4(10):2379-2399.
The immune system plays a major role in protecting the host against viral infection. Rapid initial protection is conveyed by innate immune cells, while adaptive immunity (including T lymphocytes) requires several days to develop, yet provides high specificity and long-lasting memory. Invariant natural killer T (iNKT) cells are an unusual subset of T lymphocytes, expressing a semi-invariant T cell receptor together with markers of the innate NK cell lineage. Activated iNKT cells can exert direct cytolysis and can rapidly release a variety of immune-polarizing cytokines, thereby regulating the ensuing adaptive immune response. iNKT cells recognize lipids in the context of the antigen-presenting molecule CD1d. Intriguingly, CD1d-restricted iNKT cells appear to play a critical role in anti-viral defense: increased susceptibility to disseminated viral infections is observed both in patients with iNKT cell deficiency as well as in CD1d- and iNKT cell-deficient mice. Moreover, viruses have recently been found to use sophisticated strategies to withstand iNKT cell-mediated elimination. This review focuses on CD1d-restricted lipid presentation and the strategies viruses deploy to subvert this pathway.
doi:10.3390/v4102379
PMCID: PMC3497057  PMID: 23202469
CD1d; iNKT cells; immune evasion; viruses; antigen presentation
10.  Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases 
The Journal of Experimental Medicine  2006;203(10):2293-2303.
Glycolipid ligands for invariant natural killer T cells (iNKT cells) are loaded onto CD1d molecules in the late endosome/lysosome. Accumulation of glycosphingolipids (GSLs) in lysosomal storage diseases could potentially influence endogenous and exogenous lipid loading and/or presentation and, thus, affect iNKT cell selection or function. The percentages and frequency of iNKT cells were reduced in multiple mouse models of lysosomal GSL storage disease, irrespective of the specific genetic defect or lipid species stored. Reduced numbers of iNKT cells resulted in the absence of cytokine production in response to α-galactosylceramide (α-GalCer) and reduced iNKT cell–mediated lysis of wild-type targets loaded with α-GalCer. The reduction in iNKT cells did not result from defective expression of CD1d or a lack of antigen-presenting cells. Although H-2 restricted CD4+ T cell responses were generally unaffected, processing of a lysosome-dependent analogue of α-GalCer was impaired in all the strains of mice tested. These data suggest that GSL storage may result in alterations in thymic selection of iNKT cells caused by impaired presentation of selecting ligands.
doi:10.1084/jem.20060921
PMCID: PMC2118110  PMID: 16982810
11.  PD-1:PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated iNKT cells1 
Invariant natural killer T (iNKT) cells recognize glycolipid antigens such as the marine sponge-derived glycosphingolipid α-galactosylceramide (αGalCer) presented by the CD1d protein. In vivo activation of iNKT cells with αGalCer results in robust cytokine production followed by the acquisition of an anergic phenotype. Here, we have investigated mechanisms responsible for the establishment of αGalCer-induced iNKT cell anergy. We found that αGalCer-activated iNKT cells rapidly upregulated expression of the inhibitory co-stimulatory receptor programmed death (PD)-1 at their cell surface, and this increased expression was retained for at least one month. Blockade of the interaction between PD-1 and its ligands, PD-L1 and PD-L2, at the time of αGalCer treatment prevented the induction iNKT cell anergy, but was unable to reverse established iNKT cell anergy. Consistently, injection of αGalCer into PD-1-deficient mice failed to induce iNKT cell anergy. However, blockade of the PD-1:PD-L pathway failed to prevent bacterial- or sulfatide-induced iNKT cell anergy, suggesting additional mechanisms of iNKT cell tolerance. Finally, we showed that blockade of PD-1:PD-L interactions enhanced the antimetastatic activities of αGalCer. Collectively, our findings reveal a critical role for the PD-1:PD-L costimulatory pathway in the αGalCer-mediated induction of iNKT cell anergy that can be targeted for the development of immunotherapies.
doi:10.4049/jimmunol.0803648
PMCID: PMC2709814  PMID: 19234176
12.  Invariant natural killer T cells as sensors and managers of inflammation 
Trends in immunology  2012;34(2):50-58.
Invariant natural killer T (iNKT) cells are a subset of innate-like lymphocytes that recognize glycolipid antigens bound by the major histocompatibility complex (MHC)-class-I-related protein CD1d. iNKT cells are activated early during a variety of infections and inflamma-tory diseases and contribute to the subsequent development of adaptive immune responses. Consequently, iNKT cells play a critical role in the development and resolution of inflammatory diseases and represent attractive targets for the development of immunotherapies. Recent studies have provided important insight into the mechanisms by which iNKT cells become activated in response to diverse inflammatory stimuli. These new findings should be instrumental to promote the immunomodulatory properties of iNKT cells for treatment of inflammatory diseases.
doi:10.1016/j.it.2012.08.009
PMCID: PMC3615427  PMID: 23017731
invariant natural killer T cells; CD1d; glycolipids; inflammation; immunotherapy
13.  Development of Spontaneous Anergy in Invariant Natural Killer T Cells in a Mouse Model of Dyslipidemia 
Objective
In this study, we investigated whether dyslipidemia-associated perturbed invariant natural killer T (iNKT) cell function is due to intrinsic changes in iNKT cells or defects in the ability of antigen-presenting cells to activate iNKT cells.
Methods and Results
We compared iNKT cell expansion and cytokine production in C57BL/6J (B6) and apolipoprotein E-deficient (apoE−/−) mice. In response to in vivo stimulation with α-galactosylceramide, a prototypic iNKT cell glycolipid antigen, apoE−/− mice showed significantly decreased splenic iNKT cell expansion at 3 days after injection, a profile associated with iNKT cell anergy due to chronic stimulation. This decrease in expansion and cytokine production was accompanied by a 2-fold increase in percentage of iNKT cells expressing the inhibitory marker programmed death-1 in apoE−/− mice compared with controls. However, in vivo and in vitro blockade of programmed death-1 using monoclonal antibody was not able to restore functions of iNKT cells from apoE−/− mice to B6 levels. iNKT cells from apoE−/− mice also had increased intracellular T cell receptor and Ly49 expression, a phenotype associated with previous activation. Changes in iNKT cell functions were cell autonomous, because dendritic cells from apoE−/− mice were able to activate B6 iNKT cells, but iNKT cells from apoE−/− mice were not able to respond to B6 dendritic cells.
Conclusion
These data suggest that chronic dyslipidemia induces an iNKT cell phenotype that is unresponsive to further simulation by exogenous glycolipid and that sustained unresponsiveness is iNKT cell intrinsic.
doi:10.1161/ATVBAHA.110.206045
PMCID: PMC2963029  PMID: 20539017
hypercholesterolemia; lymphocytes; immunology; lipid; antigen
14.  Type II Natural Killer T cells recognize sulfatide self-antigens using features of both innate-like and conventional T cells 
Nature immunology  2012;13(9):851-856.
Glycolipids presented by the major histocompatibility complex class I (MHC I) homolog CD1d are recognized by natural killer T (NKT) cells characterized by either a semi-invariant (type I or iNKT) or a relatively variable (type II) T cell receptor (TCR) repertoire. Here we describe the first structure of a type II NKT TCR complexed with CD1d-lysosulfatide (LSF). Both TCR α and β chains contacted the CD1d molecule with a diagonal footprint, typical of MHC-TCR interactions, while the antigen was recognized exclusively with a single TCR chain, similar to the iNKT TCR. Type II NKT cells, therefore, recognize CD1d-sulfatide complexes with a distinct recognition mechanism characterized by features of both iNKT cells as well as conventional peptide-reactive T cells.
doi:10.1038/ni.2371
PMCID: PMC3442777  PMID: 22820602
15.  α-Galactosylceramide Analogs with Weak Agonist Activity for Human iNKT Cells Define New Candidate Anti-Inflammatory Agents 
PLoS ONE  2010;5(12):e14374.
CD1d-restricted natural killer T cells with invariant T cell receptor α chains (iNKT cells) are a unique lymphocyte subset that responds to recognition of specific lipid and glycolipid antigens. They are conserved between mice and humans and exert various immunoregulatory functions through their rapid secretion of a variety of cytokines and secondary activation of dendritic cells, B cells and NK cells. In the current study, we analyzed the range of functional activation states of human iNKT cells using a library of novel analogs of α-galactosylceramide (αGalCer), the prototypical iNKT cell antigen. Measurement of cytokines secreted by human iNKT cell clones over a wide range of glycolipid concentrations revealed that iNKT cell ligands could be classified into functional groups, correlating with weak versus strong agonistic activity. The findings established a hierarchy for induction of different cytokines, with thresholds for secretion being consistently lowest for IL-13, higher for interferon-γ (IFNγ), and even higher for IL-4. These findings suggested that human iNKT cells can be intrinsically polarized to selective production of IL-13 by maintaining a low level of activation using weak agonists, whereas selective polarization to IL-4 production cannot be achieved through modulating the strength of the activating ligand. In addition, using a newly designed in vitro system to assess the ability of human iNKT cells to transactivate NK cells, we found that robust secondary induction of interferon-γ secretion by NK cells was associated with strong but not weak agonist ligands of iNKT cells. These results indicate that polarization of human iNKT cell responses to Th2-like or anti-inflammatory effects may best be achieved through selective induction of IL-13 and suggest potential discrepancies with findings from mouse models that may be important in designing iNKT cell-based therapies in humans.
doi:10.1371/journal.pone.0014374
PMCID: PMC3003687  PMID: 21179412
16.  A Humanized Monoclonal Antibody Specific for Invariant Natural Killer T (iNKT) Cells for In Vivo Depletion 
PLoS ONE  2013;8(9):e76692.
Invariant Natural Killer T (iNKT) cells are a subset of T cells recognizing glycolipid antigens presented by CD1d. Human iNKT cells express a conserved T cell receptor (TCR)-α chain (Vα24-Jα18) paired with a specific beta chain, Vβ11. The cells are both innate-like, with rapid cytokine release, and adaptive-like, including thymic positive selection. Over activation of iNKT cells can mediate tissue injury and inflammation in multiple organ systems and play a role in mediating the pathology associated with clinically important inflammatory diseases. At the same time, iNKT cell activation can play a role in protecting against infectious disease and cancer or modulate certain autoimmune diseases through its impact on both the innate and adaptive immune system. This suggests that approaches to cause iNKT cell reduction and/or depletion could treat inflammatory diseases while approaches to promote activation may have therapeutic potential in certain infections, cancer or autoimmune disease. This report summarizes the characterization of a humanized monoclonal depleting antibody (NKTT120) in the cynomolgus macaque. NKTT120 is being developed to treat iNKT mediated inflammation that is associated with chronic inflammatory conditions like sickle cell disease and asthma. NKTT120 binds to human iTCRs and to FCγRI and FCγRIII and has been shown to kill target cells in an ADCC assay at low concentrations consistent with the FCγR binding. iNKT cells were depleted within 24 hours in cynomolgus macaques, but T cell, B cell, and NK cell frequencies were unchanged. iNKT cell recovery was dose and time dependent. T cell dependent antigen responses were not impaired by NKTT120 mediated iNKT depletion as measured by response to KLH challenge. NKTT120 administration did not induce an inflammatory cytokine release at doses up to 10 mg/kg. These data support the use of NKTT120 as an intervention in inflammatory diseases where iNKT reduction or depletion could be beneficial.
doi:10.1371/journal.pone.0076692
PMCID: PMC3785425  PMID: 24086759
17.  Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice 
The Journal of Clinical Investigation  2008;118(6):2301-2315.
Invariant NKT (iNKT) cells are innate-like lymphocytes that recognize glycolipid antigens in the context of the MHC class I–like antigen-presenting molecule CD1d. In vivo activation of mouse iNKT cells with the glycolipid α-galactosylceramide (α-GalCer) results in the acquisition of a hyporesponsive (anergic) phenotype by these cells. Because iNKT cells can become activated in the context of infectious agents, here we evaluated whether iNKT cell activation by microorganisms can influence subsequent responses of these cells to glycolipid antigen stimulation. We found that mouse iNKT cells activated in vivo by multiple bacterial microorganisms, or by bacterial LPS or flagellin, became unresponsive to subsequent activation with α-GalCer. This hyporesponsive phenotype of iNKT cells required IL-12 expression and was associated with changes in the surface phenotype of these cells, reduced severity of concanavalin A–induced hepatitis, and alterations in the therapeutic activities of α-GalCer. These findings may have important implications for the development of iNKT cell–based therapies.
doi:10.1172/JCI33071
PMCID: PMC2350429  PMID: 18451996
18.  Contact-dependent interference with invariant NKT cell activation by HSV-infected cells 
Invariant CD1d-restricted natural killer T (iNKT) cells play important roles in generating protective immune responses against infections. Here, we have investigated the role of human iNKT cells in HSV-1 infection and their interaction with epidermal keratinocytes. These cells express CD1d and are the primary target of the virus. Keratinocytes loaded with α-GalCer could stimulate IFN-γ production and CD25 upregulation by iNKT cells. However, both α-GalCer- and cytokine-dependent activation of iNKT cells was impaired after coculture with HSV-1-infected cells. Interestingly, CD1d downregulation was not observed on infected keratinocytes, which were also found to inhibit TCR-independent iNKT cell activation. Further examination of the cytokine profile of iNKT/keratinocyte cocultures showed inhibition of IFN-γ, IL-5, IL-10, IL-13 and IL-17 secretion, but upregulation of IL-4 and TNF-α following the infection. Moreover, cell-to-cell contact between infected keratinocytes and iNKT cells was required for the inhibition of activation, as the cell-free supernatants containing virus did not affect activation. Productive infection of iNKT cells was however not required for the inhibitory effect. Following coculture with infected cells, iNKT cells were no longer responsive to further stimulation with α-GalCer-loaded CD1d. We found that exposure to HSV-1-infected cells resulted in impaired TCR signalling downstream of ZAP70. Additionally, infected cells upregulated the expression of the negative T cell regulator, galectin-9; however, blocking experiments indicated that the impairment of iNKT cell responses was independent of galectin-9. Thus, interference with activation of human iNKT cells by HSV-1 may represent a novel immunoevasive strategy utilized by the virus to avoid immune clearance.
doi:10.4049/jimmunol.1100218
PMCID: PMC3370127  PMID: 22581860
19.  Modulatory Function of Invariant Natural Killer T Cells in Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Multiple organ failure in SLE can be caused by immune dysfunction and deposition of autoantibodies. Studies of SLE-susceptible loci and the cellular and humoral immune responses reveal variable aberrations associated with this systemic disease. Invariant natural killer T (iNKT) cells are a unique subset of lymphocytes that control peripheral tolerance. Mounting evidence showing reductions in the proportion and activity of iNKT cells in SLE patients suggests the suppressive role of iNKT cells. Studies using murine lupus models demonstrate that iNKT cells participate in SLE progression by sensing apoptotic cells, regulating immunoglobulin production, and altering the cytokine profile upon activation. However, the dichotomy of iNKT cell actions in murine models implies complicated interactions within the body's milieu. Therefore, application of potential therapy for SLE using glycolipids to regulate iNKT cells should be undertaken cautiously.
doi:10.1155/2012/478429
PMCID: PMC3385970  PMID: 22761630
20.  CD169+ MACROPHAGES PRESENT LIPID ANTIGENS TO MEDIATE EARLY ACTIVATION OF INVARIANT NKT CELLS IN LYMPH NODES 
Nature immunology  2010;11(4):303-312.
Invariant NKT (iNKT) cells are involved in host defence against microbial infections. While it is known that iNKT cells recognize glycolipids presented by CD1d, how and where they encounter antigen in vivo remains unclear. We used multi-photon microscopy to visualize the dynamics and activation of iNKT cells in lymph nodes. Following antigen administration, iNKT cells become confined in a CD1d-dependent manner in close proximity to subcapsular sinus CD169+ macrophages. These macrophages retain, internalize and present lipid antigen, and are required for iNKT cell activation, cytokine production and expansion. Thus, CD169+ macrophages can act as bona fide antigen presenting cells controlling early iNKT cell activation and favouring fast initiation of immune responses.
doi:10.1038/ni.1853
PMCID: PMC2923071  PMID: 20228797
21.  TLR4 and NKT Cell Synergy in Immunotherapy against Visceral Leishmaniasis 
PLoS Pathogens  2012;8(4):e1002646.
NKT cells play an important role in autoimmune diseases, tumor surveillance, and infectious diseases, providing in most cases protection against infection. NKT cells are reactive to CD1d presented glycolipid antigens. They can modulate immune responses by promoting the secretion of type 1, type 2, or immune regulatory cytokines. Pathogen-derived signals to dendritic cells mediated via Toll like Receptors (TLR) can be modulated by activated invariant Natural Killer T (iNKT) cells. The terminal β-(1–4)-galactose residues of glycans can modulate host responsiveness in a T helper type-1 direction via IFN-γ and TLRs. We have attempted to develop a defined immunotherapeutic, based on the cooperative action of a TLR ligand and iNKT cell using a mouse model of visceral leishmaniasis. We evaluated the anti-Leishmania immune responses and the protective efficacy of the β-(1–4)-galactose terminal NKT cell ligand glycosphingophospholipid (GSPL) antigen of L. donovani parasites. Our results suggest that TLR4 can function as an upstream sensor for GSPL and provoke intracellular inflammatory signaling necessary for parasite killing. Treatment with GSPL was able to induce a strong effective T cell response that contributed to effective control of acute parasite burden and led to undetectable parasite persistence in the infected animals. These studies for the first time demonstrate the interactions between a TLR ligand and iNKT cell activation in visceral leishmaniasis immunotherapeutic.
Author Summary
Kala azar (visceral leishmaniasis) is a deadly disease caused by the parasitic protozoa Leishmania donovani. In absence of a suitable vaccine, the incidence of leishmaniasis has increased. The World Health Organization observes that, if the disease is not treated, the fatality rate in developing countries can be as high as 100% within 2 years. Therapy of visceral leishmaniasis can be complicated by toxic side effects, drug resistance, and the need for prolonged treatment regimens. Therefore, improved therapy for leishmaniasis remains desirable. Immunotherapy to selectively induce type 1 immune responses considered essential for resistance to leishmaniasis has shown great promise. CD1d-binding glycolipids stimulate TCR signaling and activation of invariant natural killer T (iNKT) cells. Terminal β-(1–4)-galactose residues in glycoconjugates have been identified as the TLR ligand that induces IFN-γ via TLR signaling. We have used the β-(1–4)-galactose terminal glycosphingophospholipid (GSPL) antigen from L. donovani parasites to treat infected BALB/c mice. We report that immunotherapy with GSPL induced IFN-γ, a type 1 cytokine, through the cooperative action of TLR4 and NKT-cells that contributed to effective control of acute parasite burden in the infected animals.
doi:10.1371/journal.ppat.1002646
PMCID: PMC3325212  PMID: 22511870
22.  Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection 
The Journal of Experimental Medicine  2011;208(6):1163-1177.
TLR-mediated signaling and the production of IL-12 by APCs, rather than recognition of microbial antigens, enables rapid iNKT cell responses to diverse microbial infections.
Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor–driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12–induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.
doi:10.1084/jem.20102555
PMCID: PMC3173255  PMID: 21555485
23.  Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation 
The Journal of Experimental Medicine  2012;209(5):987-1000.
Weak TCR stimulation of iNKT cells, such as that resulting from self-antigen recognition, induces histone modifications at the IFNG locus that allow the iNKT cells to subsequently produce IFN-γ in response to proinflammatory cytokines alone.
Invariant NKT cells (iNKT cells) are innate T lymphocytes that are thought to play an important role in producing an early burst of IFN-γ that promotes successful tumor immunosurveillance and antimicrobial immunity. The cellular activation processes underlying innate IFN-γ production remain poorly understood. We show here that weak T cell receptor (TCR) stimulation that does not directly activate iNKT cell IFN-γ messenger RNA transcription nevertheless induces histone H4 acetylation at specific regions near the IFNG gene locus. This renders the iNKT cells able to produce IFN-γ in an innate manner (i.e., not requiring concurrent TCR stimulation) upon exposure to IL-12 and IL-18. The iNKT cells retain the capacity for innate activation for hours to days after the initial weak TCR stimulation, although their innate responsiveness gradually declines as a function of histone deacetylation. These results explain how iNKT cells are able to mediate rapid innate IFN-γ secretion in a manner that does not require them to undergo permanent TH1 differentiation. Moreover, our results also indicate that iNKT cell motility is maintained during activation by IL-12 and IL-18. Therefore, iNKT cells activated through this pathway can continue to migrate and may thus disseminate the IFN-γ that they produce, which may amplify its impact.
doi:10.1084/jem.20111024
PMCID: PMC3348100  PMID: 22508835
24.  Impact of CD1d Deficiency on Metabolism 
PLoS ONE  2011;6(9):e25478.
Invariant natural killer T cells (iNKTs) are innate-like T cells that are highly concentrated in the liver and recognize lipids presented on the MHC-like molecule CD1d. Although capable of a myriad of responses, few essential functions have been described for iNKTs. Among the many cell types of the immune system implicated in metabolic control and disease, iNKTs seem ideally poised for such a role, yet little has been done to elucidate such a possible function. We hypothesized that lipid presentation by CD1d could report on metabolic status and engage iNKTs to regulate cellular lipid content through their various effector mechanisms. To test this hypothesis, we examined CD1d deficient mice in a variety of metabolically stressed paradigms including high fat feeding, choline-deficient feeding, fasting, and acute inflammation. CD1d deficiency led to a mild exacerbation of steatosis during high fat or choline-deficient feeding, accompanied by impaired hepatic glucose tolerance. Surprisingly, however, this phenotype was not observed in Jα18−/− mice, which are deficient in iNKTs but express CD1d. Thus, CD1d appears to modulate some metabolic functions through an iNKT-independent mechanism.
doi:10.1371/journal.pone.0025478
PMCID: PMC3183002  PMID: 21980475
25.  NKT cell costimulation: experimental progress and therapeutic promise 
Trends in molecular medicine  2010;17(2):65-77.
Invariant natural killer T (iNKT) cells are innate lymphocytes with unique specificity for glycolipid antigens and remarkable immunomodulatory properties. The role of costimulatory interactions in iNKT cell responses has recently come under scrutiny. Although iNKT cells and their prototype glycolipid agonist α-galactosylceramide (α-GalCer) have shown promise in several clinical trials conducted in patients with cancer or viral diseases, current iNKT cell-based therapies are far from effective. The concomitant targeting of T cell receptors (TCRs) and costimulatory molecules on iNKT cells represents an exciting new opportunity to optimize such therapeutic approaches. Here, we review recent advances in our understanding of iNKT cell costimulation and discuss potential treatment modalities based on the responsiveness of iNKT cells to disease-tailored glycolipids and select costimulatory ligands.
doi:10.1016/j.molmed.2010.10.007
PMCID: PMC3616392  PMID: 21087900

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