J. Exp. Med., Volume 189, Number 10, May 17, 1999 1581-1589

A Role for Neutral Sphingomyelinase-mediated Ceramide Production in T Cell Receptor-induced Apoptosis and Mitogen-activated Protein Kinase-mediated Signal Transduction

By Laura Tonnetti,^* Maria-Concetta Verí, Ezio Bonvini, and Luciano D'Adamio^*

From the ^* T-Cell Apoptosis Unit, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; and the  Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Bethesda, Maryland 20892

Studying apoptosis induced by T cell receptor (TCR) cross-linking in the T cell hybridoma, 3DO, we found both neutral sphingomyelinase activation and production of ceramide upon receptor engagement. Pharmacological inhibition of ceramide production by the fungal toxin, fumonisin B1, impaired TCR-induced interleukin (IL)-2 production and programmed cell death. Addition of either exogenous ceramide or bacterial sphingomyelinase reconstituted both responses. Moreover, specific inactivation of neutral sphingomyelinase by antisense RNA inhibited IL-2 production and mitogen-activated protein kinase activation after TCR triggering. These results suggest that ceramide production by activation of neutral sphingomyelinase is an essential component of the TCR signaling machinery.

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