BACKGROUND/AIMS: Regulatory T cell (Treg) is required for the maintenance of tolerance to various tissue antigens and to protect the host from autoimmune disorders. However, Treg may, indirectly, support cancer progression and bacterial infections. Therefore, a balance of Treg function is pivotal for adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme involved in the production of ceramide by breaking down sphingomyelin. Previous studies in T-cells have suggested that ASM is involved in CD28 signalling, T lymphocyte granule secretion, degranulation, and vesicle shedding similar to the formation of phosphatidylserine-exposing microparticles from glial cells. However, whether ASM affects the development of Treg has not yet been described. METHODS: Splenocytes, isolated Naive T lymphocytes and cultured T cells were characterized for various immune T cell markers by flow cytometery. Cell proliferation was measured by Carboxyfluorescein succinimidyl ester (CFSE) dye, cell cycle analysis by Propidium Iodide (PI), mRNA transcripts by q-RT PCR and protein expression by Western Blotting respectively. RESULTS: ASM deficient mice have higher number of Treg compared with littermate control mice. In vitro induction of ASM deficient T cells in the presence of TGF-β and IL-2 lead to a significantly higher number of Foxp3+ induced Treg (iTreg) compared with control T-cells. Further, ASM deficient iTreg has less AKT (serine 473) phosphorylation and Rictor levels compared with control iTreg. Ceramide C6 led to significant reduction of iTreg in both ASM deficient and WT mice. The reduction in iTreg leads to induction of IL-1β, IL-6 and IL-17 but not IFN-γ mRNA levels. CONCLUSION: ASM is a negative regulator of natural and iTreg.
BACKGROUND/AIMS: Regulatory T cell (Treg) is required for the maintenance of tolerance to various tissue antigens and to protect the host from autoimmune disorders. However, Treg may, indirectly, support cancer progression and bacterial infections. Therefore, a balance of Treg function is pivotal for adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme involved in the production of ceramide by breaking down sphingomyelin. Previous studies in T-cells have suggested that ASM is involved in CD28 signalling, T lymphocyte granule secretion, degranulation, and vesicle shedding similar to the formation of phosphatidylserine-exposing microparticles from glial cells. However, whether ASM affects the development of Treg has not yet been described. METHODS: Splenocytes, isolated Naive T lymphocytes and cultured T cells were characterized for various immune T cell markers by flow cytometery. Cell proliferation was measured by Carboxyfluorescein succinimidyl ester (CFSE) dye, cell cycle analysis by Propidium Iodide (PI), mRNA transcripts by q-RT PCR and protein expression by Western Blotting respectively. RESULTS:ASM deficient mice have higher number of Treg compared with littermate control mice. In vitro induction of ASM deficient T cells in the presence of TGF-β and IL-2 lead to a significantly higher number of Foxp3+ induced Treg (iTreg) compared with control T-cells. Further, ASM deficient iTreg has less AKT (serine 473) phosphorylation and Rictor levels compared with control iTreg. Ceramide C6 led to significant reduction of iTreg in both ASM deficient and WT mice. The reduction in iTreg leads to induction of IL-1β, IL-6 and IL-17 but not IFN-γ mRNA levels. CONCLUSION:ASM is a negative regulator of natural and iTreg.
Authors: Matthias Hose; Anne Günther; Hanna Abberger; Salina Begum; Marek Korencak; Katrin A Becker; Jan Buer; Astrid M Westendorf; Wiebke Hansen Journal: Front Immunol Date: 2019-05-31 Impact factor: 7.561
Authors: Jana Meiners; Vittoria Palmieri; Robert Klopfleisch; Jana-Fabienne Ebel; Lukasz Japtok; Fabian Schumacher; Ayan Mohamud Yusuf; Katrin A Becker; Julia Zöller; Matthias Hose; Burkhard Kleuser; Dirk M Hermann; Richard N Kolesnick; Jan Buer; Wiebke Hansen; Astrid M Westendorf Journal: Front Immunol Date: 2019-06-19 Impact factor: 7.561
Authors: Cosima Rhein; Iulia Zoicas; Lena M Marx; Stefanie Zeitler; Tobias Hepp; Claudia von Zimmermann; Christiane Mühle; Tanja Richter-Schmidinger; Bernd Lenz; Yesim Erim; Martin Reichel; Erich Gulbins; Johannes Kornhuber Journal: Int J Mol Sci Date: 2021-05-27 Impact factor: 5.923
Authors: Ujjwal M Mahajan; Elisabetta Goni; Enno Langhoff; Qi Li; Eithne Costello; William Greenhalf; Stephan Kruger; Steffen Ormanns; Christopher Halloran; Paula Ganeh; Manuela Marron; Felix Lämmerhirt; Yue Zhao; Georg Beyer; Frank-Ulrich Weiss; Matthias Sendler; Christiane J Bruns; Thomas Kohlmann; Thomas Kirchner; Jens Werner; Jan G D'Haese; Michael von Bergwelt-Baildon; Volker Heinemann; John P Neoptolemos; Markus W Büchler; Claus Belka; Stefan Boeck; Markus M Lerch; Julia Mayerle Journal: JNCI Cancer Spectr Date: 2019-08-16