Cell-intrinsic ceramides determine T cell function during melanoma progression

Cell-intrinsic ceramides determine T cell function during melanoma progression

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Acid sphingomyelinase (Asm) and acid ceramidase (Ac) are parts of the sphingolipid Study protocol: developing and evaluating an interactive web platform to teach children hunting, shooting and firearms safety: a randomized controlled trial metabolism.Asm hydrolyzes sphingomyelin to ceramide, which is further metabolized to sphingosine by Ac.Ceramide generates ceramide-enriched platforms that are involved in receptor clustering within cellular membranes.However, the impact of cell-intrinsic ceramide on T cell function is not well characterized.

By using T cell-specific Asm- or Ac-deficient mice, with reduced or elevated ceramide levels in T cells, we identified ceramide to play a crucial role in T cell function in vitro and in vivo.T cell-specific ablation of Asm in Smpd1fl/fl/Cd4cre/+ (Asm/CD4cre) mice resulted in enhanced tumor progression associated with impaired T cell responses, whereas Asah1fl/fl/Cd4cre/+ (Ac/CD4cre) mice showed reduced tumor growth rates and elevated T cell activation compared to the respective controls upon tumor transplantation.Further in vitro analysis revealed that decreased ceramide content supports CD4+ regulatory T cell differentiation and interferes with cytotoxic activity of CD8+ T cells.In contrast, elevated ceramide concentration in CD8+ T cells from Ac/CD4cre mice was associated with enhanced cytotoxic activity.

Strikingly, ceramide co-localized with the T cell receptor CONTESTATION OF CHEMICAL CASTRATION PUNISHMENT FOR CHILD SEX OFFENDERS (TCR) and CD3 in the membrane of stimulated T cells and phosphorylation of TCR signaling molecules was elevated in Ac-deficient T cells.Hence, our results indicate that modulation of ceramide levels, by interfering with the Asm or Ac activity has an effect on T cell differentiation and function and might therefore represent a novel therapeutic strategy for the treatment of T cell-dependent diseases such as tumorigenesis.