Cell-intrinsic ceramides determine T cell function during melanoma progression

Abstract

Acid sphingomyelinase (Asm) and acid ceramidase (Ac) are parts of the sphingolipid 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 Asmflox/flox/CD4cre mice resulted in enhanced tumor progression associated with impaired T cell responses, whereas Acflox/flox/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 Acflox/flox/CD4cre mice was associated with enhanced cytotoxic activity. Strikingly, ceramide co-localized with the T cell receptor (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.

Sphingolipids in thyroid eye disease

“…A recent study using T cell-specific acid sphingomyelinase-or acid ceramidase-deficient mice revealed that T cell-specific ablation of acid sphingomyelinase resulted in reduced ceramide levels in T cells and an impairment of T cell responses, whereas T cell specific deletion of the acid ceramidase elevated T cell activation (98). Decreased ceramide concentrations promoted differentiation of CD4 + regulatory T cells, but also negatively interfered with cytotoxic activity of CD8 + T cells, which was improved by elevated ceramide concentrations (98).…”

“…A recent study using T cell-specific acid sphingomyelinase-or acid ceramidase-deficient mice revealed that T cell-specific ablation of acid sphingomyelinase resulted in reduced ceramide levels in T cells and an impairment of T cell responses, whereas T cell specific deletion of the acid ceramidase elevated T cell activation (98). Decreased ceramide concentrations promoted differentiation of CD4 + regulatory T cells, but also negatively interfered with cytotoxic activity of CD8 + T cells, which was improved by elevated ceramide concentrations (98). The studies also linked the T cell receptor (TCR/CD3) complex to ceramide-enriched membrane domains, since ceramide co-localized with the TCR/ CD3 complex forming an immune synapse in stimulated T cells, an event that seems to regulate the strength of TCR/CD3 signaling (99).…”

Multi-omic validation of the cuproptosis-sphingolipid metabolism network: modulating the immune landscape in osteosarcoma

“…Sphingolipids and their metabolic derivatives are involved in regulating processes including apoptosis and autophagy (13,14). The metabolism of sphingolipids also plays a role in the interactions between tumor cells and the immune system, influencing tumor cell behavior and the functionality of immune responses (15)(16)(17). Regulation of these metabolic pathways may reveal new therapeutic strategies for osteosarcoma.…”