Distinct antigen-presenting cells explain the cytokine bias of α-galactosylceramide variants in vivo

• Published in: The Journal of immunology (1950) 2012-03, 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102414

α-galactosylceramide (αGC) 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 antigen-presenting cell-types explained the cytokine bias in vivo . Whereas NKT stimulation by αGC required CD1d expression by 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 antigen-presenting cell targeting in vivo .