title: Administration of alpha-galactosylceramide impairs the survival of dendritic cell subpopulations in vivo.
abstract: In this study, we examine whether recognition of α-GalCer presented on CD1d-expressing DCs and B cells in vivo elicits the cytotoxic activity of iNKT cells and elimination of α-GalCer-presenting cells. We report that i.v. injection of α-GalCer induced a decrease in the percentage and number of splenic CD8(+)Langerin(+) DCs, while CD8(-) DCs were not affected. The decline in CD8(+) DC numbers was clearly detectable by 15 h after α-GalCer injection, was maximal at 24-48 h, returned to normal by day 7, and was accompanied by a reduced cross-presentation of OVA protein given i.v. to specific CD8(+) T cells in vitro. The decrease in the numbers of CD8(+) DCs required iNKT cells but was independent of perforin, Fas, or IFN-γ, as it was observed in mice deficient in each of these molecules. In contrast, treatment with a TNF-α-neutralizing antibody was effective at reducing the decline in CD8(+) DC numbers and DC activation. Treatment with immunostimulatory CpG ODN also resulted in DC activation and a decreased number of CD8(+) DCs; however, the decline in DC number was a result of down-regulation of CD11c and CD8 and did not require iNKT cells or TNF-α. Although CD8(+)Langerin(+) DCs appeared to be selectively affected by α-GalCer treatment, they were not required for early iNKT cell responses, as their prior depletion did not prevent the increase in serum TNF-α and IL-4 observed after α-GalCer treatment. Thus, iNKT cells regulate the survival of CD8(+) DCs through a mechanism that does not appear to involve direct cell killing.
authors.affiliation: Malaghan Institute of Medical Research, Victoria University, Wellington, New Zealand.
authors.forename: Helen M A
authors.initials: HM
authors.lastname: Simkins
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hyde
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Farrand
authors.forename: Monique L
authors.initials: ML
authors.lastname: Ong
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hermans
authors.forename: Franca
authors.initials: F
authors.lastname: Ronchese
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D055610:Antigens, CD1d; D005699:Galactosylceramides; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma