title: Colocalization of a CD1d-Binding Glycolipid with a Radiation-Attenuated Sporozoite Vaccine in Lymph Node-Resident Dendritic Cells for a Robust Adjuvant Effect.
abstract: A CD1d-binding glycolipid, α-Galactosylceramide (αGalCer), activates invariant NK T cells and acts as an adjuvant. We previously identified a fluorinated phenyl ring-modified αGalCer analog, 7DW8-5, displaying nearly 100-fold stronger CD1d binding affinity. In the current study, 7DW8-5 was found to exert a more potent adjuvant effect than αGalCer for a vaccine based on radiation-attenuated sporozoites of a rodent malaria parasite, Plasmodium yoelii, also referred to as irradiated P. yoelii sporozoites (IrPySpz). 7DW8-5 had a superb adjuvant effect only when the glycolipid and IrPySpz were conjointly administered i.m. Therefore, we evaluated the effect of distinctly different biodistribution patterns of αGalCer and 7DW8-5 on their respective adjuvant activities. Although both glycolipids induce a similar cytokine response in sera of mice injected i.v., after i.m. injection, αGalCer induces a systemic cytokine response, whereas 7DW8-5 is locally trapped by CD1d expressed by dendritic cells (DCs) in draining lymph nodes (dLNs). Moreover, the i.m. coadministration of 7DW8-5 with IrPySpz results in the recruitment of DCs to dLNs and the activation and maturation of DCs. These events cause the potent adjuvant effect of 7DW8-5, resulting in the enhancement of the CD8(+) T cell response induced by IrPySpz and, ultimately, improved protection against malaria. Our study is the first to show that the colocalization of a CD1d-binding invariant NK T cell-stimulatory glycolipid and a vaccine, like radiation-attenuated sporozoites, in dLN-resident DCs upon i.m. conjoint administration governs the potency of the adjuvant effect of the glycolipid.
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY 10016;
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry, Hunter College of The City University of New York, New York, NY 10065;
authors.forename: Akira
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY 10016;
authors.forename: Chasity D
authors.initials: CD
authors.lastname: Andrews
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109;
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Douglass
authors.initials: D
authors.lastname: Wu
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY 10016;
authors.forename: Tiffany
authors.initials: T
authors.lastname: Tsao
authors.affiliation: Department of Pathology, New York University, New York, NY 10016;
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Structural Biology Resource Center, The Rockefeller University, New York, NY 10065;
authors.forename: Deena
authors.initials: D
authors.lastname: Oren
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY 10016;
authors.forename: Neal N
authors.initials: NN
authors.lastname: Padte
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; Academia Sinica, Taipei 115-74, Taiwan, Republic of China.
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109;
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY 10016;
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY 10016; mtsuji@adarc.org.
authors.forename: Moriya
authors.initials: M
authors.lastname: Tsuji
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000469:parasitology; D017780:Malaria Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology; D010967:Plasmodium yoelii / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D034101:Sporozoites / Q000276:immunology
chemical_list: C000603808:7DW8-5 glycolipid; D000276:Adjuvants, Immunologic; D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D016207:Cytokines; D005699:Galactosylceramides; D017780:Malaria Vaccines; C493154:alpha-galactosylceramide