CaRLO — Cancer Research Library Online

1

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Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency

Porubsky,S. ; Speak,A.O. ; Luckow,B. ; [et al.]

Proceedings of the National Academy of Sciences of the United States of America 104 (14), 5977-5982

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Keywords: A3galt2, ALPHA-CHAIN, antigen presentation, CD1d, dendritic cell, EXPRESSION, GAL-ALPHA(1,3)GAL, gly

Abstract: CD1d-restricted natural killer T(NKT) cells, expressing the invariant T cell antigen receptor (TCR) chain encoded by V alpha 14-J alpha 18 gene segments in mice and V alpha 24-J alpha 18 in humans [invariant NKT (iNKT) cells], contribute to immunoregulatory processes, such as tolerance, hostdefense, and tumor surveillance. iNKT cells are positively selected in the thymus by CD1d molecules expressed by CD4+/ CD8(+) cortical thymocytes. However, the identity of the endogenous lipid(s) responsible for positive selection of iNKT cells remains unclear. One candidate lipid proposed to play a role in positive selection is isoglobotrilhexosylceramide (iGb3). However, no direct evidence for its physiological role has been provided. Therefore, to directly investigate the role of iGb3 in iNKT cell selection, we have generated mice deficient in iGb3 synthase [iGb3S, also known as alpha 1-3galactosyltransferase 2 (A3galt2)]. These mice developed, grew, and reproduced normally and exhibited no overt behavioral abnormalities. Consistent with the notion that iGb3 is synthesized only by iGb3S, lack of iGb3 in the dorsal root ganglia of iGb3S-deficient mice (iGb3S(-/-)), as compared with iGb3S(+/-) mice, was confirmed. iGb3S(-/-) mice showed normal numbers of iNKT cells in the thymus, spleen, and liver with selected TCR V beta chains identical to controls. Upon administration of alpha-galactosylceramide, activation of iNKT and dendritic cells was similar in iGb3S(-/-) and iGb3S(+/-) mice, as measured by up-regulation of CD69 as well as intracellular IL-4 and IFN-gamma in iNKT cells, up-regulation of CD86 on dendritic cells, and rise in serum concentrations of IL-4, IL-6, IL-10, IL-12p70, IFN-gamma, TNF-alpha, and Ccl2/MCP-1. Our results strongly suggest that iGb3 is unlikely to be an endogenous CD1d lipid ligand determining thymic iNKT selection.

Type of Publication: Journal article published

PubMed ID: 17372206

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=4988

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Accumulation of glucosylceramide in murine testis, caused by inhibition of beta-glucosidase 2 - Implications for spermatogenesis

Walden,C.M. ; Sandhoff,R. ; Chuang,C.C. ; [et al.]

Journal of Biological Chemistry 282 (45), 32655-32664

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Keywords: brain ; CELLS ; IN-VITRO ; CELL ; IN-VIVO ; INHIBITION ; VITRO ; VIVO ; DRUG ; ACCUMULATION ; MICE ; BIOLOGY ; MOLECULAR-BIOLOGY ; treatment ; MOUSE ; NUMBER ; BETA ; LOCALIZATION ; HUMAN LIVER ; GLUCOSE ; sensitivity ; TESTIS ; molecular biology ; molecular ; CHAIN ; DEFICIENT MICE ; GERM-CELLS ; CERAMIDE ; development ; LEVEL ; ENZYME ; STRAINS ; USA ; DEFICIENT ; Male ; COMPOUND ; in vivo ; spleen ; - ; ACID BETA-GLUCOSIDASE ; ALKYLATED IMINO SUGARS ; GANGLIOSIDE BIOSYNTHESIS ; MALE CONTRACEPTION ; MALE-FERTILITY ; N-BUTYLDEOXYNOJIRIMYCIN ; NONLYSOSOMAL GLUCOSYLCERAMIDASE ; STORAGE DISEASE

Abstract: One of the hallmarks of male germ cell development is the formation of a specialized secretory organelle, the acrosome. This process can be pharmacologically disturbed in C57BL/ 6 mice, and thus infertility can be induced, by small molecular sugar- like compounds ( alkylated imino sugars). Here the biochemical basis of this effect has been investigated. Our findings suggest that in vivo alkylated imino sugars primarily interact with the non- lysosomal glucosylceramidase. This enzyme cleaves glucosylceramide into glucose and ceramide, is sensitive to imino sugars in vitro, and has been characterized as beta- glucosidase 2 ( GBA2). Imino sugars raised the level of glucosylceramide in brain, spleen, and testis, in a dose- dependent fashion. In testis, multiple species of glucosylceramide were similarly elevated, those having long acyl chains ( C16 - 24), as well as those with very long polyunsaturated acyl chains ( C28 - 30: 5). Both of these GlcCer species were also increased in the testes from GBA2- deficient mice. When considering that the very long polyunsaturated sphingolipids are restricted to germ cells, these results indicate that in the testis GBA2 is present in both somatic and germ cells. Furthermore, in all mouse strains tested imino sugar treatment caused a rise in testicular glucosylceramide, even in a number of strains, of which the males remain fertile after drug administration. Therefore, it appears that acrosome formation can be derailed by accumulation of glucosylceramide in an extralysosomal localization, and that the sensitivity of male germ cells to glucosylceramide is genetically determined

Type of Publication: Journal article published

PubMed ID: 17848577

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=5330

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Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans

de Santo,C. ; Salio,M. ; Masri,S.H. ; [et al.]

Journal of Clinical Investigation 118 (12), 4036-4048

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Keywords: CELLS ; EXPRESSION ; SURVIVAL ; CELL ; human ; IN-VIVO ; EXPOSURE ; MORTALITY ; MICE ; ACTIVATION ; RESPONSES ; INFECTION ; MECHANISM ; DENDRITIC CELLS ; IMMUNE-RESPONSES ; virus ; NO ; HEALTH ; HUMANS ; antigen presentation ; INDIVIDUALS ; immune response ; IMMUNE-RESPONSE ; INFLAMMATORY RESPONSES ; SUPPRESSOR ; elderly ; USA ; ENGLAND ; EXPANSION ; NATURAL-KILLER ; PUBLIC-HEALTH ; MEDICINE ; IFN-GAMMA PRODUCTION ; outcome ; response ; ALPHA-GALACTOSYLCERAMIDE ; Crosstalk ; INNATE IMMUNE-RESPONSE ; KILLER T-CELLS ; MURINE CYTOMEGALOVIRUS ; Myeloid cell ; myeloid cells ; myeloid-derived suppressor cells ; SUPPRESSOR-CELLS ; TUMOR IMMUNOSURVEILLANCE

Abstract: infection with influenza A virus (IAV) presents a substantial threat to public health worldwide, with young, elderly, and immunodeficient individuals being particularly susceptible. Inflammatory responses play an important role in the fatal outcome of IAV infection, but the mechanism remains unclear. We demonstrate here that the absence of invariant NKT (iNKT) cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality. Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The crosstalk between iNKT and MDSCs was CD1d- and CD40-dependent. Furthermore, IAV infection and exposure to TLR agonists relieved the suppressive activity of MDSCs. Finally, we extended these results to humans by demonstrating the presence of myeloid cells with suppressive activity in the PBLs of individuals infected with IAV and showed that their suppressive activity is substantially reduced by iNKT cell activation. These findings identify what we believe to be a novel immunomodulatory role of iNKT cells, which we suggest could be harnessed to abolish the immunosuppressive activity of MDSCs during IAV infection

DOI: 10.1172/JCI36264

Type of Publication: Journal article published

PubMed ID: 19033672

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=5747

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4

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Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis - A link to ceramide synthase-3

Rabionet,M. ; van der Spoel,A.C. ; Chuang,C.C. ; [et al.]

Journal of Biological Chemistry 283 (19), 13357-13369

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Keywords: CELLS ; EXPRESSION ; CELL ; GENE ; GENES ; MICE ; COMPLEX ; FAMILY ; BIOLOGY ; MOLECULAR-BIOLOGY ; MATURATION ; ACID ; MOUSE ; PROGRESSION ; spermatogenesis ; glycosylation ; SERIES ; TESTIS ; POLYUNSATURATED FATTY-ACIDS ; molecular biology ; molecular ; CHAIN ; FAMILIES ; DEFICIENT MICE ; LEVEL ; MUTANTS ; USA ; GANGLIOSIDES ; ENGLAND ; FAMILY-MEMBERS ; GLUCOSYLCERAMIDE ; SEMINIFEROUS EPITHELIUM

Abstract: Previously, it was found that a novel class of neutral fucosylated glycosphingolipids (GSLs) is required for male fertility. These lipids contain very long-chain (C26-C32) polyunsaturated (4-6 double bonds) fatty acid residues (VLC-PUFAs). To assess the role of these complex GSLs in spermatogenesis, we have now investigated with which of the testicular cell types these lipids are associated. During postnatal development, complex glycosylated and simple VLC-PUFA sphingolipids were first detectable at day 15, when the most advanced germ cells are pachytene spermatocytes. Their synthesis is most likely driven by ceramide synthase-3. This enzyme is encoded by the Cers3/Lass3 gene (longevity assurance genes), and out of six members of this gene family, only Cers3 mRNA expression was limited to germ cells, where it was up-regulated more than 700-fold during postnatal testicular maturation. Increasing levels of neutral complex VLC-PUFA GSLs also correlated with the progression of spermatogenesis in a series of male sterile mutants with arrests at different stages of spermatogenesis. Remarkably, fucosylation of the complex VLC-PUFA GSLs was not essential for spermatogenesis, as fucosylation- deficient mice produced nonfucosylated versions of the complex testicular VLC-PUFA GSLs, had complete spermatogenesis, and were fertile. Nevertheless, sterile Galgt1(-/-) mice, with a defective meiotic cytokinesis and a subsequent block in spermiogenesis, lacked complex but contained simple VLC-PUFA GSLs, as well as VLC-PUFA ceramides and sphingomyelins, indicating that the latter lipids are not sufficient for completion of spermatogenesis. Thus, our data imply that both glycans and the particular acyl chains of germinal sphingolipids are relevant for proper completion of meiosis

Type of Publication: Journal article published

PubMed ID: 18308723

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=6815

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5

Electronic Resource

Synthesis of 1,5-dideoxy-3-O-(α-D-mannopyranosyl)-1,5-imino-D-mannitol and 1,5-dideoxy-3-O-(α-D-glucopyranosyl)-1,5-imino-D-mannitol: Powerful inhibitors of endomannosidase

Ardron, H. ; Butters, T.D. ; Platt, F.M. ; [et al.]

Amsterdam : Elsevier

Tetrahedron: Asymmetry 4 (1993), S. 2011-2024

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ISSN: 0957-4166

Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Topics: Chemistry and Pharmacology

Type of Medium: Electronic Resource

URL: http://linkinghub.elsevier.com/retrieve/pii/S0957-4166(00)82250-8

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6

Electronic Resource

Analysis and isolation of human transferrin receptor using the OKT-9 monoclonal antibody covalently crosslinked to magnetic beads

Karlsson, G.B. ; Platt, F.M.

Amsterdam : Elsevier

Analytical Biochemistry 199 (1991), S. 219-222

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ISSN: 0003-2697

Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Topics: Biology , Chemistry and Pharmacology

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1016/0003-2697(91)90093-9

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