TY - JOUR
T1 - Glycolipids that elicit IFN-γ-biased responses from natural killer T cells
AU - Tyznik, Aaron J.
AU - Farber, Elisa
AU - Girardi, Enrico
AU - Birkholz, Alysia
AU - Li, Yali
AU - Chitale, Sampada
AU - So, Regina
AU - Arora, Pooja
AU - Khurana, Archana
AU - Wang, Jing
AU - Porcelli, Steven A.
AU - Zajonc, Dirk M.
AU - Kronenberg, Mitchell
AU - Howell, Amy R.
N1 - Funding Information:
We would like to thank Dr. Petra Krause for technical and graphical assistance. We would like to thank Stanford Synchrotron Radiation Lightsource BL 9-2 for remote data collection. This work was supported by National Institutes of Health (NIH) RO1 grants AI45053, AI71922 (M.K.), F32 AI80087 (A.T.), Investigator award from the Cancer Research Institute and NIH grant RO1 AI074952 (D.Z), and NIH RO1 grant GM 087136 (A.H).
PY - 2011/12/23
Y1 - 2011/12/23
N2 - Natural killer T (NKT) cells recognize glycolipids presented by CD1d. The first antigen described, α-galactosyl ceramide (αGalCer), is a potential anticancer agent whose activity depends upon IFN-γ secretion. We report two analogs of αGalCer based on a naturally occurring glycosphingolipid, plakoside A. These compounds induce enhanced IFN-γ that correlates with detergent-resistant binding to CD1d and an increased stability of the lipid-CD1d complexes on antigen-presenting cells. Structural analysis on one of the analogs indicates that it is more deeply bound inside the CD1d groove, suggesting tighter lipid-CD1d interactions. To our knowledge, this is the first example in which structural information provides an explanation for the increased lipid-CD1d stability, likely responsible for the Th1 bias. We provide insights into the mechanism of IFN-γ-inducing compounds, and because our compounds activate human NKT cells, they could have therapeutic utility.
AB - Natural killer T (NKT) cells recognize glycolipids presented by CD1d. The first antigen described, α-galactosyl ceramide (αGalCer), is a potential anticancer agent whose activity depends upon IFN-γ secretion. We report two analogs of αGalCer based on a naturally occurring glycosphingolipid, plakoside A. These compounds induce enhanced IFN-γ that correlates with detergent-resistant binding to CD1d and an increased stability of the lipid-CD1d complexes on antigen-presenting cells. Structural analysis on one of the analogs indicates that it is more deeply bound inside the CD1d groove, suggesting tighter lipid-CD1d interactions. To our knowledge, this is the first example in which structural information provides an explanation for the increased lipid-CD1d stability, likely responsible for the Th1 bias. We provide insights into the mechanism of IFN-γ-inducing compounds, and because our compounds activate human NKT cells, they could have therapeutic utility.
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U2 - 10.1016/j.chembiol.2011.10.015
DO - 10.1016/j.chembiol.2011.10.015
M3 - Article
C2 - 22195564
AN - SCOPUS:84555202450
SN - 1074-5521
VL - 18
SP - 1620
EP - 1630
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 12
ER -