Abstract

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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Publisher Full Text

Authors

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

Institution

Committee on Immunology, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. baili@ustc.edu.cn

Source

Journal of immunology (Baltimore, Md. : 1950) 188:7 2012 Apr 1 pg 3053-61

MeSH

Animals
Antigen Presentation
Antigen-Presenting Cells
Antigens, CD1d
B-Lymphocytes
Cells, Cultured
Dendritic Cells
Feedback, Physiological
Galactosylceramides
Gene Expression Regulation
Interferon-gamma
Interleukin-12
Macrophages
Mice
Mice, Inbred C57BL
Natural Killer T-Cells
Specific Pathogen-Free Organisms
Structure-Activity Relationship

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22393151