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 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.
Committee on Immunology, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. firstname.lastname@example.org
SourceJournal of immunology (Baltimore, Md. : 1950) 188:7 2012 Apr 1 pg 3053-61
Gene Expression Regulation
Mice, Inbred C57BL
Natural Killer T-Cells
Specific Pathogen-Free Organisms
Pub Type(s)Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't