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We have hypothesized that ASM modulates CD4<jats:sup>+<\/jats:sup> T-cell receptor activation and impacts immune responses. We first observed interactions of ASM with the intracellular domains of both CD3 and CD28. ASM further mediates T-cell proliferation after anti-CD3\/CD28 antibody stimulation and alters CD4<jats:sup>+<\/jats:sup> T-cell activation signals by generating ceramide. We noted that various pharmacological inhibitors of ASM or knockdown of ASM using small hairpin RNA inhibit CD3\/CD28-mediated CD4<jats:sup>+<\/jats:sup> T-cell proliferation and activation. Furthermore, such blockade of ASM bioactivity by biochemical inhibitors and\/or molecular-targeted knockdown of ASM broadly abrogate T-helper cell responses. In conclusion, we detail immune, pivotal roles of ASM in adaptive immune T-cell responses, and propose that these pathways might provide novel targets for the therapy of autoimmune and inflammatory diseases.<\/jats:p>","DOI":"10.1038\/cddis.2015.178","type":"journal-article","created":{"date-parts":[[2015,7,23]],"date-time":"2015-07-23T12:48:02Z","timestamp":1437655682000},"page":"e1828-e1828","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Role of acid sphingomyelinase bioactivity in human CD4+ T-cell activation and immune responses"],"prefix":"10.1038","volume":"6","author":[{"given":"A","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Kokkotou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S C","family":"Robson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,7,23]]},"reference":[{"key":"BFcddis2015178_CR1","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1016\/j.febslet.2009.11.083","volume":"584","author":"EH Schuchman","year":"2010","unstructured":"Schuchman EH . 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