Glycolipids that elicit IFN-γ-biased responses from natural killer T cells

Chem Biol. 2011 Dec 23;18(12):1620-30. doi: 10.1016/j.chembiol.2011.10.015.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigens, CD1d / chemistry
  • Antigens, CD1d / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Galactosylceramides / chemical synthesis
  • Galactosylceramides / chemistry
  • Galactosylceramides / pharmacology
  • Glycolipids / chemical synthesis
  • Glycolipids / chemistry*
  • Glycolipids / pharmacology*
  • Humans
  • Interferon-gamma / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Natural Killer T-Cells / drug effects*
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism*
  • Protein Structure, Tertiary

Substances

  • Antigens, CD1d
  • Antineoplastic Agents
  • Galactosylceramides
  • Glycolipids
  • alpha-galactosylceramide
  • Interferon-gamma

Associated data

  • PDB/3TVM