Journal of immunology (Baltimore, Md. : 1950) 2012 Apr 1;188(7):3053-61. Epub 2012 Mar 5.
Bai, L; Constantinides, MG; Thomas, SY; Reboulet, R; Meng, F; Koentgen, F; Teyton, L; Savage, PB; Bendelac, A
Committee on Immunology, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
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.