CERAMIDE-INDEPENDENT CD28 AND TCR SIGNALING BUT REDUCED IL-2 SECRETION IN T-CELLS OF ACID SPHINGOMYELINASE-DEFICIENT MICE

Ceramide generated by lysosomal acid sphingomyelinase (aSMase) has bee n proposed to contribute to CD28 co-stimulatory signaling pathways. We used an aSMase-deficient mouse line (asmase(-/-)) to elucidate the ro le of the aSMase in splenocytes stimulated with either a combination o f anti-CD3 and anti-CD28 antibodies, the lectin concanavalin A (Con A) or the superantigen staphylococcal enterotoxin B. All stimuli were sh own to induce IL-2 expression, Con A additionally triggered the expres sion of high-affinity IL-2 receptor. However, in asmase(-/-) mice secr etion of IL-2 was significantly reduced, whereas the intracellular IL- 2 levels were elevated. Proliferation of anti-Cd3/anti-CD28 or Con A-s timulated aSMase-deficient splenocytes was reduced up to 50 % after 72 h in comparison to wildtype cells. We conclude that ceramide generate d by aSMase is not involved in CD28 signal transduction, but rather a perturbation of the secretory system is responsible for the impaired p roliferation of aSMase-deficient splenocytes.