Fine specificity of natural killer T cells against GD3 ganglioside and identification of GM3 as an inhibitory natural killer T-cell ligand

Immunology. 2008 Jan;123(1):145-55. doi: 10.1111/j.1365-2567.2007.02760.x.

Abstract

GD3, a ganglioside expressed on melanoma, is the only tumour-associated glycolipid described to date that can induce a CD1d-restricted natural killer T (NKT)-cell response. We analysed the fine specificity of GD3-reactive NKT cells and discovered that immunization with GD3 induced two populations of GD3-reactive NKT cells. One population was CD4+ CD8- and was specific for GD3; the other population was CD4- CD8- and cross-reacted with GM3 in a CD1d-restricted manner, but did not cross-react with GM2, GD2, or lactosylceramide. This indicated that the T-cell receptors reacting with GD3 recognize glucose-galactose linked to at least one N-acetyl-neuraminic acid but will not accommodate a terminal N-acetylgalactosamine. Immunization with GM2, GM3, GD2, or lactosylceramide did not induce an NKT-cell response. Coimmunization of GM3-loaded antigen-presenting cells (APCs) with GD3-loaded APCs suppressed the NKT-cell response to GD3 in a CD1d-restricted manner. This suppressive effect was specific for GM3 and was a local effect lasting 2-4 days. In vitro, GM3-loaded APCs also suppressed the interleukin-4 response, but not the interferon-gamma response, of NKT cells to alpha-galactosylceramide. However, there was no effect on the T helper type 2 responses of conventional T cells. We found that this suppression was not mediated by soluble factors. We hypothesize that GM3 induces changes to the APC that lead to suppression of T helper type 2-like NKT-cell responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigens, CD1 / immunology
  • Antigens, CD1d
  • Cross Reactions / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • G(M3) Ganglioside / immunology*
  • Galactosylceramides / immunology
  • Gangliosides / immunology*
  • Immune Tolerance / immunology
  • Immunization / methods
  • Interleukin-4 / immunology
  • Killer Cells, Natural / immunology*
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocyte Subsets / immunology*

Substances

  • Antigens, CD1
  • Antigens, CD1d
  • Epitopes, T-Lymphocyte
  • G(M3) Ganglioside
  • Galactosylceramides
  • Gangliosides
  • Ligands
  • alpha-galactosylceramide
  • Interleukin-4
  • ganglioside, GD3