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iNKT Cells (inkt + cell)

Distribution by Scientific Domains

Medical Sciences	92%

Selected Abstracts

Impact of class A, B and C CpG-oligodeoxynucleotides on in vitro activation of innate immune cells in human immunodeficiency virus-1 infected individuals

IMMUNOLOGY, Issue 4 2007
Jeffrey A. Martinson
Summary Oligodeoxynucleotides (ODN) with unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG-ODNs) stimulate Toll-like receptor 9 (TLR9) in plasmacytoid dendritic cells (pDC) and B cells and activate innate and adaptive immunity. Three classes of synthetic CpG-ODNs, class A, B and C, activate cells through TLR9; our goal was to evaluate their effect on cells from human immunodeficiency virus (HIV)-1+ individuals. We compared the frequencies and the unstimulated activation status of immune effector cells in HIV-1+ and HIV-1, individuals. Fewer pDC, myeloid dendritic cells (mDC), B cells, natural killer (NK) cells and invariant natural killer T cells (iNKT) were present in HIV-1+ peripheral blood mononuclear cells (PBMC) and their baseline activation status was higher than HIV-1, PBMC. Exposure of HIV-1+ PBMC to all classes of CpG-ODNs led to activation and maturation of pDC based on CD86, CD80, and CD83 expression similar to that of cells from HIV-1, individuals. The percentage of CpG-ODN stimulated pDC that express CD40 was dramatically higher when cells were obtained from HIV-1+ than from HIV-1, individuals. B-lymphocytes were activated similarly in HIV-1+ and HIV-1, individuals. mDC, NK and iNKT cell, which lack TLR9, were indirectly activated. Interferon-, (IFN-,) and interferon inducible protein 10 (IP-10) secretion was induced by class A or C but not class B CpG-ODN, but the concentrations were less than those produced by HIV-1, PBMC. HIV-1 infected individuals have fewer innate effector cells that are chronically activated, but these cells can be further activated by CpG-ODN, which suggests that synthetic CpG-ODNs could be used to enhance the immune system in HIV-1 infected individuals. [source]

CD4+CD25hi regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

INTERNATIONAL JOURNAL OF CANCER, Issue 8 2007
Johan W. Molling
Abstract CD4+CD25hiCTLA4+FoxP3+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self antigens and increased circulating frequencies have been reported in various types of cancers. Circulating invariant natural killer T-cells (iNKT) are reduced in cancer patients and low iNKT frequency is related to poor prognosis. It is not yet clear whether high Treg numbers and low iNKT cell numbers pose an increased risk for the progression of premalignant lesions or whether Treg and iNKT cell numbers are influenced by dysplasia. We therefore studied prospectively the relation between iNKT cell and Treg frequencies and the natural course of human papillomavirus type 16 (HPV16) induced pre-malignant cervical dysplasia in 82 patients who participated in a nonintervention cohort study of women with abnormal cytology. Treg frequencies were significantly increased in women who had persistent HPV16 infection. Within the HPV16 persistence group there was no difference in Treg frequencies among patients who developed a CIN3 lesion and patients who did not progress to CIN3. Furthermore, Treg frequencies were increased in patients who had detectable HPV16 E7 specific IL-2 producing T-helper cells, which suggests a causal role of HPV infection in Treg development in parallel with HPV16 specific T helper cells. No evidence was found for a role for iNKT cells in persistence of HPV16 and progression of HPV16 induced CIN lesions. However, HPV-persistence-associated Tregs may explain the inefficacy of concomitant persistence associated immunity and may contribute to subsequent progression to neoplasia. © 2007 Wiley-Liss, Inc. [source]

,-GalCer ameliorates listeriosis by accelerating infiltration of Gr-1+ cells into the liver

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010
Masashi Emoto
Abstract ,-Galactosylceramide (,-GalCer) activates invariant (i)NKT cells, which in turn stimulate immunocompetent cells. Although activation of iNKT cells appears critical for regulation of immune responses, it remains elusive whether protection against intracellular bacteria can be induced by ,-GalCer. Here, we show that ,-GalCer treatment ameliorates murine listeriosis, and inhibits inflammation following Listeria monocytogenes infection. Liver infiltration of Gr-1+ cells and ,/, T cells was accelerated by ,-GalCer treatment. Gr-1+ cell and ,/, T-cell depletion exacerbated listeriosis in ,-GalCer-treated mice, and this effect was more pronounced after depletion of Gr-1+ cells than that of ,/, T cells. Although GM-CSF and IL-17 were secreted by NKT cells after ,-GalCer treatment, liver infiltration of Gr-1+ cells was not prevented by neutralizing mAb. In parallel to the numerical increase of CD11b+Gr-1+ cells in the liver following ,-GalCer treatment, CD11b,Gr-1+ cells were numerically reduced in the bone marrow. In addition, respiratory burst in Gr-1+ cells was enhanced by ,-GalCer treatment. Our results indicate that ,-GalCer-induced antibacterial immunity is caused, in part, by accelerated infiltration of Gr-1+ cells and to a lesser degree of ,/, T cells into the liver. We also suggest that the infiltration of Gr-1+ cells is caused by an accelerated supply from the bone marrow. [source]

Leishmania donovani -induced expression of signal regulatory protein , on Kupffer cells enhances hepatic invariant NKT-cell activation

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2010
Lynette Beattie
Abstract Signal regulatory protein , (SIRP,) and its cognate ligand CD47 have been documented to have a broad range of cellular functions in development and immunity. Here, we investigated the role of SIRP,,CD47 signalling in invariant NKT (iNKT) cell responses. We found that CD47 was required for the optimal production of IFN-, from splenic iNKT cells following exposure to the ,GalCer analogue PBS-57 and in vivo infection of mice with Leishmania donovani. Surprisingly, although SIRP, was undetectable in the liver of uninfected mice, the hepatic iNKT-cell response to infection was also impaired in CD47,/, mice. However, we found that SIRP, was rapidly induced on Kupffer cells following L. donovani infection, via a mechanism involving G-protein-coupled receptors. Thus, we describe a novel amplification pathway affecting cytokine production by hepatic iNKT cells, which may facilitate the breakdown of hepatic tolerance after infection. [source]

Development and maturation of invariant NKT cells in the presence of lysosomal engulfment

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009
Tiziana Plati
Abstract A defect in invariant NKT (iNKT) cell selection was hypothesized in lysosomal storage disorders (LSD). Accumulation of glycosphingolipids (GSL) in LSD could influence lipid loading and/or presentation causing entrapment of endogenous ligand(s) within storage bodies or competition of the selecting ligand(s) by stored lipids for CD1d binding. However, when we analyzed the iNKT cell compartment in newly tested LSD animal models that accumulate GSL, glycoaminoglycans or both, we observed a defective iNKT cell selection only in animals affected by multiple sulfatase deficiency, in which a generalized aberrant T-cell development, rather than a pure iNKT defect, was present. Mice with single lysosomal enzyme deficiencies had normal iNKT cell development. Thus, GSL/glycoaminoglycans storage and lysosomal engulfment are not sufficient for affecting iNKT cell development. Rather, lipid ligand(s) or storage compounds, which are affected in those LSD lacking mature iNKT cells, might indeed be relevant for iNKT cell selection. [source]

Immediate antigen-specific effector functions byTCR-transgenic CD8+ NKT cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006
Gerhard Wingender
Abstract Only recently have natural antigens for CD1d-dependent, invariant V,14+ natural killer T (iNKT) cells been identified. Similar data for CD1d-independent and CD8+ NKT cell populations are still missing. Here, we show that the MHC class,I-restricted CD8+ TCR-transgenic mouse lines OT-I, P14 and H-Y contain a significant proportion of transgenic CD8+ NK1.1+ T,cells. In liver, most of NK1.1+ T,cells express CD8,, homodimers. Transgenic NKT cells did not bind invariant V,14-to-J,18 TCR rearrangement (V,14i)-specific CD1d/,-galactosylceramide tetramers and the frequency of iNKT cells was severely reduced. The activated cell surface phenotype and the distribution of transgenic NKT cells in vivo were similar to that reported for iNKT cells. The OT-I and P14 CD8+ NKT cells recognized their cognate antigen in the context of H2-Kb and produced cytokines shortly after TCR stimulation. Importantly, transgenic NKT cells exerted immediate antigen-specific cytotoxicity in vitro and in vivo. Our results demonstrate the presence of transgenic CD8+ NKT cells in MHC class,I-restricted TCR-transgenic animals, which are endowed with rapid antigen-specific effector functions. These data imply that experiments studying naive T,cell function in TCR-transgenic animals should be interpreted with caution, and that such animals could be utilized for studying CD8+ NKT cell function in an antigen-specific manner. [source]

Rapid and reliable generation of invariant natural killer T-cell lines in vitro

IMMUNOLOGY, Issue 3 2009
Asako Chiba
Summary Several tools have proved useful in the study of invariant natural killer T (iNKT) cells, including CD1d-deficient mice, J,281-deficient mice, synthetic lipid antigens and antigen-loaded CD1d tetramers. However, the generation and examination of long-term primary murine iNKT cell lines in vitro has been challenging. Here, we show the rapid generation of iNKT cell lines from splenic iNKT cells of V,14 T-cell receptor (TCR) transgenic (Tg) mice. These purified iNKT cells were stimulated by bone marrow-derived dendritic cells (BMDCs) loaded with ,-galactosylceramide (,GalCer) and cultured with interleukin (IL)-2 and IL-7. iNKT cells proliferated dramatically, and the cell number exhibited a 100-fold increase within 2 weeks and a 105 -fold increase in 8 weeks after repeated stimulation with ,GalCer. The iNKT cell lines consisted of iNKT cells expressing V, chains including V,8.1/8.2, V,14, V,10, V,6 and V,7, and responded to stimulation with ,GalCer presented both by BMDCs and by plate-bound CD1d. In addition, the iNKT cell lines produced interferon (IFN)-, when activated by lipopolysaccharide (LPS) or CpG oligodeoxynucleotide (ODN)-stimulated BMDCs. Further, we show that iNKT cell lines produced cytokines in response to microbial antigens. In summary, high-yield iNKT cell lines were generated very rapidly and robustly expanded, and these iNKT cells responded to both TCR and cytokine stimulation in vitro. Given the desire to study primary iNKT cells for many purposes, these iNKT cell lines should provide an important tool for the study of iNKT cell subsets, antigen and TCR specificity, activation, inactivation and effector functions. [source]

Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11

IMMUNOLOGY, Issue 1 2007
Carlos J. Montoya
Summary Identification of human CD1d-restricted T-cell receptor (TCR)-invariant natural killer T (iNKT) cells has been dependent on utilizing combinations of monoclonal antibodies or CD1d tetramers, which do not allow for the most specific analysis of this T-cell subpopulation. A novel monoclonal antibody (clone 6B11), specific for the invariant CDR3 loop of human canonical V,24J,18 TCR , chain, was developed and used to specifically characterize iNKT cells. In healthy individuals studied for up to 1 year, a wide but stable frequency of circulating iNKT cells (range: 0·01,0·92%) was observed, with no differences in frequency by gender. Four stable iNKT cell subsets were characterized in peripheral blood based on the expression of CD4 and CD8, with CD8+ iNKT cells being a phenotypic and functionally different subset from CD4+ and double negative iNKT cells; in particular, LAG-3 was preferentially expressed on CD8+ iNKT cells. In addition, a strong negative linear correlation between the frequency of total iNKT cells and percentage of the CD4+ subset was observed. In terms of their potential association with disease, patients at risk for type 1 diabetes had significantly expanded frequencies of double negative iNKT cells when compared to matched controls and first-degree relatives. Moreover, peripheral blood CD4+ iNKT cells were the highest producers of interleukin-4, while the production of interferon-, and tumour necrosis factor-, was similar amongst all iNKT cell subsets. These differences in iNKT cell subsets suggest that in humans the relative ratio of iNKT cell subsets may influence susceptibility vs. resistance to immune-mediated diseases. [source]

Innate self recognition by an invariant, rearranged T-cell receptor and its immune consequences

IMMUNOLOGY, Issue 2 2003
Aleksandar K. Stanic
Summary This review attempts to illuminate the glycolipid antigen presentation properties of CD1d, how CD1d controls the function of natural T (iNKT) cells and how CD1d and iNKT cells interact to jump-start the immune system. It is postulated that the CD1d-iNKT cell system functions as a sensor, sensing alterations in cellular lipid content by virtue of its affinity for such ligands. The presentation of a neo-self glycolipid, presumably by infectious assault of antigen-presenting cells, activates iNKT cells, which promptly release pro-inflammatory and anti-inflammatory cytokines and jump-start the immune system. [source]

CD4+CD25hi regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

Invariant natural killer T cells are natural regulators of murine spondylarthritis

ARTHRITIS & RHEUMATISM, Issue 4 2010
Peggy Jacques
Objective To investigate the role of invariant natural killer T (iNKT) cells in TNF,ARE/+ mice, an animal model of spondylarthritis (SpA) with both gut and joint inflammation. Methods The frequency and activation of iNKT cells were analyzed on mononuclear cells from the lymph nodes and livers of mice, using flow cytometry with ,-galactosylceramide/CD1d tetramers and quantitative polymerase chain reaction for the invariant V,14,J,18 rearrangement. Bone marrow,derived dendritic cells (DCs) were obtained by expansion of primary cells with granulocyte,macrophage colony-stimulating factor followed by coculture with iNKT cell hybridomas, and interleukin-2 release into the cocultures was then measured by enzyme-linked immunosorbent assay (ELISA). Cytokine levels were determined by ELISA or cytometric bead array analyses of freshly isolated DCs and iNKT cells in mixed cocultures. TNF,ARE/+ mice were backcrossed onto J,18,/, and CD1d,/, mice, and disease onset was evaluated by clinical scoring, positron emission tomography, and histology. CD1d levels were analyzed on mononuclear cells in paired blood and synovial fluid samples from patients with SpA compared with healthy control subjects. Results In the absence of iNKT cells, symptoms of gut and joint inflammation in TNF,ARE/+mice were aggravated. Invariant NKT cells were activated during the course of the disease. This was linked to an enrichment of inflammatory DCs, characterized by high levels of CD1d, particularly at draining sites of inflammation. A similar increase in CD1d levels was observed on DCs from patients with SpA. Inflammatory DCs from TNF,ARE/+ mice stimulated iNKT cells to produce immunomodulatory cytokines, in the absence of exogenous stimulation. Prolonged, continuous exposure, but not short-term exposure, to tumor necrosis factor (TNF) was found to be responsible for the enhanced DC,NKT cell crosstalk. Conclusion This mode of iNKT cell activation represents a natural counterregulatory mechanism for the dampening of TNF-driven inflammation. [source]

Nonglycosidic Agonists of Invariant NKT Cells for Use as Vaccine Adjuvants

CHEMMEDCHEM, Issue 2 2009
Gopal Reddy Dr.
Abstract Based on the crystal structures of human ,-GalCer,CD1d and iNKT,,-GalCer,CD1d complexes, nonglycosidic analogues of ,-GalCer were synthesized. They activate iNKT cells resulting in dendritic cell maturation and the priming of antigen-specific T and B cells. Therefore, they are attractive adjuvants in vaccination strategies for cancer and infectious diseases. [source]