Cell-intrinsic ceramides determine T cell function during melanoma progression Journal Article
| Authors: | Hose, M.; Günther, A.; Naser, E.; Schumacher, F.; Schönberger, T.; Falkenstein, J.; Papadamakis, A.; Kleuser, B.; Becker, K. A.; Gulbins, E.; Haimovitz-Friedman, A.; Buer, J.; Westendorf, A. M.; Hansen, W. |
| Article Title: | 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 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 (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. © 2022, Hose, Günther et al. |
| Keywords: | t cells; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; metabolism; animals; mice; melanoma; inflammation; immunology; receptors, antigen, t-cell; sphingolipids; sphingosine; lymphocyte antigen receptor; ceramide; ceramides |
| Journal Title: | eLife |
| Volume: | 11 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2022-11-25 |
| Start Page: | e83073 |
| Language: | English |
| DOI: | 10.7554/eLife.83073 |
| PUBMED: | 36426850 |
| PROVIDER: | scopus |
| PMCID: | PMC9699697 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 January 2023 -- Source: Scopus |
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