| First Author | Hose M | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 36426850 | Mgi Jnum | J:333409 |
| Mgi Id | MGI:7387771 | Doi | 10.7554/eLife.83073 |
| Citation | Hose M, et al. (2022) Cell-intrinsic ceramides determine T cell function during melanoma progression. Elife 11 |
| abstractText | 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 Smpd1(fl/fl)/Cd4(cre/+) (Asm/CD4cre) mice resulted in enhanced tumor progression associated with impaired T cell responses, whereas Asah1(fl/fl)/Cd4(cre/+) (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 (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. |
