Distinct APCs explain the cytokine bias of α-galactosylceramide variants in vivo

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 N...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2012-04, Vol.188 (7), p.3053-3061
Main Authors: Bai, Li, Constantinides, Michael G, Thomas, Seddon Y, Reboulet, Rachel, Meng, Fanyong, Koentgen, Frank, Teyton, Luc, Savage, Paul B, Bendelac, Albert
Format: Article
Language:English
Subjects:
Animals
Antigen Presentation
Antigen-Presenting Cells - classification
Antigen-Presenting Cells - immunology
Antigens, CD1d - biosynthesis
Antigens, CD1d - genetics
Antigens, CD1d - immunology
B-Lymphocytes - immunology
Cells, Cultured - drug effects
Cells, Cultured - immunology
Cells, Cultured - metabolism
Dendritic Cells - immunology
Feedback, Physiological
Galactosylceramides - chemistry
Galactosylceramides - immunology
Galactosylceramides - pharmacology
Gene Expression Regulation
Interferon-gamma - metabolism
Interleukin-12 - metabolism
Macrophages - immunology
Mice
Mice, Inbred C57BL
Natural Killer T-Cells - drug effects
Natural Killer T-Cells - immunology
Natural Killer T-Cells - metabolism
Specific Pathogen-Free Organisms
Structure-Activity Relationship
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1102414