Seminar: Prof. Sibylle Schneider-Schaulies

The neutral sphingomyelinase in modulating thresholds of T cell activation

Date:
20 May 2015 13:30 hrs. - 14:30 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
The neutral sphingomyelinase in modulating thresholds of T cell activation
Speaker(s):

Prof. Sibylle Schneider-Schaulies, Institute for Virology and Immunobiology, University of Würzburg, Germany

Host(s):

Dr. Alessandra Cambi, Dept. of Tumor Immunology, Radboudumc

20-05-2015 13:30:0020-05-2015 14:30:00Europe/AmsterdamThe neutral sphingomyelinase in modulating thresholds of T cell activation Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

undefinedundefinedundefinedundefinedPhysical and functional T cell paralysis is a major feature in immunosuppression caused by measles virus (MV) by mere surface contact with it target cells indicating the virus signals via receptor interaction to silence T cells. Sphingomyelins are major components of the plasma membrane and are hydrolyzed to ceramides upon activation of acid (ASM) or neutral (NSM) sphingomyelinases which is associated with profound biophysical alterations of the membrane. We established that MV contact promotes sequential activation of NSM and ASM and this almost exclusively accounted for the loss of stimulated actin re-organisation in T cells. Because formation of ceramide-enriched membrane domains in response to sphingomyelinase activation acts to sort receptors and associated signalosomes we reasoned  that MV-mediated activation of this pathway might contribute to aberrant relay of TCR signaling. We were able to show that MV exposure causes rapid, prolonged activation of NSM2 (but not ASM) and ceramide accumulation within the IS. Moreover, genetic ablation of the enzyme efficiently rescued MV-induced loss of TCR induced spreading responses, however, only partially, loss of proliferative responses.

In line with exaggerated ceramide release and IS localization being inhibitory, this sphingolipid was largely excluded from the IS in co-stimulated healthy T cells, where it was compartmentalized to the lamellum. We established for the first time that T cell co-stimulation caused a transient activation of NSM, which co-segregated with ceramides in the lamellum. Indicating a physiologic role of NSM activation in T cell activation, genetic ablation was associated with T cell hyper-responsiveness to co-stimulation as revealed by spreading responses, accumulation of tyrosine phosphorylated proteins, Ca2+-mobilisation and proliferation upon genetic ablation of the enzyme.

We therefore propose that co-stimulation mediated NSM activation in T cells is timely and spatially stringently controlled and acts to dampen TCR signaling by targeting as yet unknown signalosome components. If timely and quantitatively aberrantly induced, the dampening activity of the NSM turns into an inhibitory and may essentially take part in T cell suppression as seen upon MV exposure.

 



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