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CD4<jats:sup>+<\/jats:sup> Foxp3<jats:sup>+<\/jats:sup> regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4<jats:sup>+<\/jats:sup> T (Tconv) cells. In ASM-deficient (<jats:italic>Smpd1<\/jats:italic>\n                  <jats:sup>\u2212\/\u2212<\/jats:sup>) as compared to wt mice, membranes of T cells contain 7\u201310-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4<jats:sup>+<\/jats:sup> T cells in ASM-deficient mice and their suppressive activity <jats:italic>in vitro<\/jats:italic> are increased. Moreover, <jats:italic>in vitro<\/jats:italic> stimulation of ASM-deficient T cells in the presence of TGF-\u03b2 and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4<jats:sup>+<\/jats:sup> T cells within a few days. This fast alteration of the balance between T cell populations <jats:italic>in vitro<\/jats:italic> is due to the elevated cell death of Tconv cells and protection of the CD25<jats:sup>high<\/jats:sup> Treg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.<\/jats:p>","DOI":"10.1515\/hsz-2018-0159","type":"journal-article","created":{"date-parts":[[2018,6,16]],"date-time":"2018-06-16T22:15:46Z","timestamp":1529187346000},"page":"1175-1182","source":"Crossref","is-referenced-by-count":22,"title":["CD4<sup>+<\/sup> Foxp3<sup>+<\/sup> regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase"],"prefix":"10.1515","volume":"399","author":[{"given":"J\u00fcrgen","family":"Schneider-Schaulies","sequence":"first","affiliation":[{"name":"Institute for Virology and Immunobiology , University of W\u00fcrzburg , Versbacher Str. 7 , D-97078 W\u00fcrzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Beyersdorf","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology , University of W\u00fcrzburg , Versbacher Str. 7 , D-97078 W\u00fcrzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2018,6,19]]},"reference":[{"key":"2023040406465656007_j_hsz-2018-0159_ref_001_w2aab3b7b5b1b6b1ab2b2b1Aa","doi-asserted-by":"crossref","unstructured":"Abdel Shakor, A.B., Atia, M.M., Kwiatkowska, K., and Sobota, A. 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