Beta-glycosphingolipids-mediated lipid raft alteration is associated with redistribution of NKT cells and increased intrahepatic CD8+ T lymphocyte trapping

Gadi Lalazar, Ami Ben Ya'acov, Noa Eliakim-Raz, Dan M. Livovsky, Orit Pappo, Sarah Preston, Lidya Zolotarov, and Yaron Ilan

Liver Unit, Hebrew University - Hadassah Medical Center, Jerusalem 91120

Corresponding Author: ilan{at}hadassah.org.il

The aim of this study was to determine the effect of $beta$ -glycosphingolipids on intra-hepatic natural killer T lymphocyte (NKT) regulatory function and on lymphocyte trapping via alteration of cell membrane lipid rafts. Immune-mediated colitis was induced by intracolonic instillation of trinitrobenzenesulfonic-acid (TNBS). Mice were treated with $beta$ -lactosylceramide (LC), $beta$ -glucosylceramide (GC), $beta$ -galactosylceramide (GLC), ceramide, or a combination of both GC and LC (IGL), or solvent alone. Lipid rafts were investigated by FACS analysis of ganglioside-GM1 and fluorescence microscopy of structure. Administration of $beta$ -glycosphingolipids resulted in an increased intrahepatic/peripheral NKT ratio, increased intrahepatic CD8+ lymphocyte trapping, decreased serum IFN- $gamma$ levels and decreased serum IFN $gamma$ /IL-10 ratio. Administration of GC, LC, or IGL significantly altered the levels of GM1, a key marker of lipid rafts, on NKT regulatory lymphocytes. The immune modulatory effect of $beta$ -glycosphingolipids was associated with increased survival and significant alleviation of colitis as determined by improvement in both the macroscopic and microscopic scores. In conclusion, administration of $beta$ -glycosphingolipids increased NKT regulatory lymphocyte redistribution and intrahepatic CD8+ T lymphocyte trapping, resulting in alleviation of immune-mediated colitis. The effects of these naturally occurring compounds were associated with modification of the T lymphocyte lipid raft structure, which is a site for immune modulation.

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