title: Distinct APCs explain the cytokine bias of α-galactosylceramide variants in vivo.
abstract: α-Galactosylceramide represents a new class of vaccine adjuvants and immunomodulators that stimulate NKT cells to secrete Th1 and Th2 cytokines. Synthetic variants with short or unsaturated acyl chains exhibit a striking Th2 bias in vivo but no evidence of defect in TCR signaling or stimulation of NKT cells in vitro. Using cd1d1(fl/fl) mice, we demonstrated that distinct APC types explained the cytokine bias in vivo. Whereas NKT stimulation by α-Galactosylceramide required CD1d expression by dendritic cells (DCs), presentation of the Th2 variants was promiscuous and unaffected by DC-specific ablation of CD1d. This DC-independent stimulation failed to activate the feedback loop between DC IL-12 and NK cell IFN-γ, explaining the Th2 bias. Conversely, forced presentation of the Th2 variants by DC induced high IL-12. Thus, lipid structural variations that do not alter TCR recognition can activate distinct Th1 or Th2 cellular networks by changing APC targeting in vivo.
authors.affiliation: Committee on Immunology, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. baili@ustc.edu.cn
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.forename: Michael G
authors.initials: MG
authors.lastname: Constantinides
authors.forename: Seddon Y
authors.initials: SY
authors.lastname: Thomas
authors.forename: Rachel
authors.initials: R
authors.lastname: Reboulet
authors.forename: Fanyong
authors.initials: F
authors.lastname: Meng
authors.forename: Frank
authors.initials: F
authors.lastname: Koentgen
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000145:classification / Q000276:immunology*; D055610:Antigens, CD1d / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D025461:Feedback, Physiological; D005699:Galactosylceramides / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013329:Structure-Activity Relationship
chemical_list: D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D018664:Interleukin-12; D007371:Interferon-gamma