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

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Journal of immunology (Baltimore, Md. : 1950) 2012 Apr 1;188(7):3053-61. Epub 2012 Mar 5.

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

L Bai;MG Constantinides;SY Thomas;R Reboulet;F Meng;F Koentgen;L Teyton;PB Savage;A Bendelac

Committee on Immunology, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.

Service type: Knockout mice


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.

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