Distinct APCs Explain the Cytokine Bias of &agr;-Galactosylceramide Variants In Vivo.

&agr;-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 cdldlfl/fl mice, we demonstrated that distinct APC types explained the cytokine bias in vivo. Whereas NKT stimulation by &agr;-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-&ggr;, 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 Thl or Th2 cellular networks by changing APC targeting in vivo. [ABSTRACT FROM AUTHOR]