title: Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4+ Conventional versus Foxp3+ Regulatory T Cells.
abstract: 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.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany.
authors.forename: Claudia
authors.identifier: 0000-0002-3933-8370
authors.initials: C
authors.lastname: Hollmann
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Werner
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany.
authors.forename: Elita
authors.initials: E
authors.lastname: Avota
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany.
authors.forename: Dajana
authors.initials: D
authors.lastname: Reuter
authors.affiliation: Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; and.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; and.
authors.forename: Burkhard
authors.identifier: 0000-0002-1888-9595
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Institute for Molecular Biology, University of Duisburg-Essen, D-45122 Essen, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Institute for Molecular Biology, University of Duisburg-Essen, D-45122 Essen, Germany.
authors.forename: Katrin Anne
authors.initials: KA
authors.lastname: Becker
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany.
authors.forename: Jürgen
authors.identifier: 0000-0001-7713-5518
authors.initials: J
authors.lastname: Schneider-Schaulies
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany; niklas.beyersdorf@vim.uni-wuerzburg.de.
authors.forename: Niklas
authors.initials: N
authors.lastname: Beyersdorf
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology* / Q000821:virology; D018106:CD28 Antigens / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D008457:Measles / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018103:Morbillivirus / Q000276:immunology*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000821:virology
chemical_list: D018106:CD28 Antigens; D015704:CD4 Antigens; D002518:Ceramides; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; C112980:acid sphingomyelinase-1; C577975:ASMase, mouse; D013108:Sphingomyelin Phosphodiesterase