title: Quantitative and qualitative differences in the in vivo response of NKT cells to distinct alpha- and beta-anomeric glycolipids.
abstract: NKT cells represent a unique subset of immunoregulatory T cells that recognize glycolipid Ags presented by the MHC class I-like molecule CD1d. Because of their immunoregulatory properties, NKT cells are attractive targets for the development of immunotherapies. The prototypical NKT cell ligand alpha-galactosylceramide (alpha-GalCer), originally isolated from a marine sponge, has potent immunomodulatory activities in mice, demonstrating therapeutic efficacy against metastatic tumors, infections, and autoimmune diseases, but also has a number of adverse side effects. In vivo administration of alpha-GalCer to mice results in the rapid activation of NKT cells, which is characterized by cytokine secretion, surface receptor down-regulation, expansion, and secondary activation of a variety of innate and adaptive immune system cells. In this study, we have evaluated the in vivo immune response of mice to a set of structural analogues of alpha-GalCer. Our results show that, contrary to current thinking, beta-anomeric GalCer can induce CD1d-dependent biological activities in mice, albeit at lower potency than alpha-anomeric GalCer. In addition, we show that the response of NKT cells to distinct GalCer differs not only quantitatively, but also qualitatively. These findings indicate that NKT cells can fine-tune their immune responses to distinct glycolipid Ags in vivo, a property that may be exploited for the development of effective and safe NKT cell-based immunotherapies.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Vrajesh V
authors.initials: VV
authors.lastname: Parekh
authors.forename: Avneesh K
authors.initials: AK
authors.lastname: Singh
authors.forename: Michael T
authors.initials: MT
authors.lastname: Wilson
authors.forename: Danyvid
authors.initials: D
authors.lastname: Olivares-Villagómez
authors.forename: Jelena S
authors.initials: JS
authors.lastname: Bezbradica
authors.forename: Hiroko
authors.initials: H
authors.lastname: Inazawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ehara
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Sakai
authors.forename: Isao
authors.initials: I
authors.lastname: Serizawa
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Chyung-Ru
authors.initials: CR
authors.lastname: Wang
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D006017:Glycolipids / Q000008:administration & dosage* / Q000276:immunology* / Q000627:therapeutic use; D007073:Immunoglobulin E / Q000097:blood; D007274:Injections, Intraperitoneal; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011609:Psychosine / Q000008:administration & dosage / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D005699:Galactosylceramides; D006017:Glycolipids; D011948:Receptors, Antigen, T-Cell; D011609:Psychosine; D007073:Immunoglobulin E; C103873:KRN 7000