Bai, AKokkotou, EZheng, YRobson, S C2016-01-042015Bai, A, E Kokkotou, Y Zheng, and S C Robson. 2015. “Role of acid sphingomyelinase bioactivity in human CD4+ T-cell activation and immune responses.” Cell Death & Disease 6 (7): e1828. doi:10.1038/cddis.2015.178. http://dx.doi.org/10.1038/cddis.2015.178.2041-4889http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993605Acid sphingomyelinase (ASM), a lipid hydrolase enzyme, has the potential to modulate various cellular activation responses via the generation of ceramide and by interaction with cellular receptors. We have hypothesized that ASM modulates CD4+ 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+ 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+ 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.en-USJournal Article2016-01-0410.1038/cddis.2015.178