Abstract

Lipid rafts reportedly have a role in coalescing key signaling molecules into the immunological synapse during T cell activation, thereby modulating T cell receptor (TCR) signaling activity. Recent findings suggest that a correlation may exist between increased levels of glycosphingolipids (GSLs) in the lipid rafts of T cells and a heightened response of those T cells toward activation. Here, we show that lowering the levels of GSLs in CD4(+) T cells using a potent inhibitor of glucosylceramide synthase (Genz-122346) led to a moderation of the T cell response toward activation. TCR proximal signaling events, such as phosphorylation of Lck, Zap70 and LAT, as well as early Ca(2+) mobilization, were attenuated by treatment with Genz-122346. Concomitant with these events were significant reductions in IL-2 production and T cell proliferation. Similar findings were obtained with CD4(+) T cells isolated from transgenic mice genetically deficient in GM3 synthase activity. Interestingly, lowering the GSL levels in CD4(+) T cells by either pharmacological inhibition or disruption of the gene for GM3 synthase also specifically inhibited the differentiation of T cells to the Th(17) lineage but not to other Th subsets in vitro. Taken together with the recently reported effects of Raftlin deficiency on Th(17) differentiation, these results strongly suggest that altering the GSL composition of lipid rafts modulates TCR signaling activity and affects Th(17) differentiation.

Highlights

  • Ods of T cell activation that seek to cluster the T cell receptor (TCR) complex, such as with an anti-CD3 antibody [3,4,5,6,7,8,9,10,11,12,13]

  • Similar results were obtained with T cells isolated from a transgenic mouse that had been rendered deficient in GM3 synthase activity

  • We have shown that lowering the levels of GSLs, which are major components of lipid rafts, using a potent glucosylceramide synthase inhibitor (Genz-123346) attenuated TCR signaling, T cell activation, and differentiation to the Th17 lineage

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Summary

Glycosphingolipids in T Cell Signaling and Differentiation

Treatment of T cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthase, attenuates TCR signaling and T cell activation as indicated by a reduction in the expression of markers of T cell activation and secretion of IFN-␥ [26] This effect is not observed with myriocin, an inhibitor of serine palmitoyltransferase that acts at an earlier step of sphingolipid synthesis, suggesting that inhibition of GSL synthesis at different nodes in the biosynthetic pathway can lead to distinctive outcomes. We observed that a deficiency in GSLs inhibited Th17 differentiation in vitro without affecting the other Th subsets examined Taken together, these results indicate that altering the lipid composition of lipid rafts has profound effects on T cell activation and differentiation

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