TY  - JOUR
A1  - Hollmann, Claudia
A1  - Werner, Sandra
A1  - Avota, Elita
A1  - Reuter, Dajana
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Becker, Katrin Anne
A1  - Schneider-Schaulies, Jürgen
A1  - Beyersdorf, Niklas
T1  - Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4(+) Conventional versus Foxp3(+) Regulatory T Cells
JF  - The journal of immunology
N2  - CD4(+) Foxp3(+) regulatory T cells (Tregs) depend on CD28 signaling for their survival and function, a receptor that has been previously shown to activate the acid sphingomyelinase (Asm)/ceramide system. In this article, we show that the basal and CD28-induced Asm activity is higher in Tregs than in conventional CD4(+) T cells (Tconvs) of wild-type (wt) mice. In Asm-deficient (Smpd1(-/-); Asm(-/-)) mice, as compared with wt mice, the frequency of Tregs among CD4(+) T cells, turnover of the effector molecule CTLA-4, and their suppressive activity in vitro were increased. The biological significance of these findings was confirmed in our Treg-sensitive mouse model of measles virus (MV) CNS infection, in which we observed more infected neurons and less MV-specific CD8(+) T cells in brains of Asm(-/-) mice compared with wt mice. In addition to genetic deficiency, treatment of wt mice with the Asm inhibitor amitriptyline recapitulated the phenotype of Asm-deficient mice because it also increased the frequency of Tregs among CD4(+) T cells. Reduced absolute cell numbers of Tconvs after inhibitor treatment in vivo and extensive in vitro experiments revealed that Tregs are more resistant toward Asm inhibitor-induced cell death than Tconvs. Mechanistically, IL-2 was capable of providing crucial survival signals to the Tregs upon inhibitor treatment in vitro, shifting the Treg/Tconv ratio to the Treg side. Thus, our data indicate that Asm-inhibiting drugs should be further evaluated for the therapy of inflammatory and autoimmune disorders.
Y1  - 2016
U6  - https://doi.org/10.4049/jimmunol.1600691
SN  - 0022-1767
SN  - 1550-6606
VL  - 197
SP  - 3130
EP  - 3141
PB  - American Assoc. of Immunologists
CY  - Bethesda
ER  -