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

• Published in: The Journal of immunology (1950) Vol. 188; no. 7; pp. 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: Journal Article
• Language: English
• Published: United States 01.04.2012
• 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102414

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.