Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4+ Conventional versus Foxp3+ Regulatory T Cells

• Published in: The Journal of immunology (1950) 2016-10, Vol.197 (8), p.3130-3141
• Main Authors: Hollmann, Claudia, Werner, Sandra, Avota, Elita, Reuter, Dajana, Japtok, Lukasz, Kleuser, Burkhard, Gulbins, Erich, Becker, Katrin Anne, Schneider-Schaulies, Jürgen, Beyersdorf, Niklas
• Format: Article
• Language: English
• Subjects: Animals; Brain - immunology; Brain - virology; CD28 Antigens - metabolism; CD4 Antigens - metabolism; Cell Differentiation; Cell Survival; Cells, Cultured; Ceramides - metabolism; Forkhead Transcription Factors - metabolism; Interleukin-2 - metabolism; Lymphocyte Activation; Measles - enzymology; Measles - immunology; Measles virus; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbillivirus - immunology; Sphingomyelin Phosphodiesterase - genetics; Sphingomyelin Phosphodiesterase - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - virology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - virology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600691

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.