title: Induction of membrane ceramides: a novel strategy to interfere with T lymphocyte cytoskeletal reorganisation in viral immunosuppression.
abstract: Silencing of T cell activation and function is a highly efficient strategy of immunosuppression induced by pathogens. By promoting formation of membrane microdomains essential for clustering of receptors and signalling platforms in the plasma membrane, ceramides accumulating as a result of membrane sphingomyelin breakdown are not only essential for assembly of signalling complexes and pathogen entry, but also act as signalling modulators, e. g. by regulating relay of phosphatidyl-inositol-3-kinase (PI3K) signalling. Their role in T lymphocyte functions has not been addressed as yet. We now show that measles virus (MV), which interacts with the surface of T cells and thereby efficiently interferes with stimulated dynamic reorganisation of their actin cytoskeleton, causes ceramide accumulation in human T cells in a neutral (NSM) and acid (ASM) sphingomyelinase-dependent manner. Ceramides induced by MV, but also bacterial sphingomyelinase, efficiently interfered with formation of membrane protrusions and T cell spreading and front/rear polarisation in response to beta1 integrin ligation or alphaCD3/CD28 activation, and this was rescued upon pharmacological or genetic ablation of ASM/NSM activity. Moreover, membrane ceramide accumulation downmodulated chemokine-induced T cell motility on fibronectin. Altogether, these findings highlight an as yet unrecognised concept of pathogens able to cause membrane ceramide accumulation to target essential processes in T cell activation and function by preventing stimulated actin cytoskeletal dynamics.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gassert
authors.forename: Elita
authors.initials: E
authors.lastname: Avota
authors.forename: Harry
authors.initials: H
authors.lastname: Harms
authors.forename: Georg
authors.initials: G
authors.lastname: Krohne
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Sibylle
authors.initials: S
authors.lastname: Schneider-Schaulies
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008459:Measles virus / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*
chemical_list: D002518:Ceramides; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; C519633:SMPD2 protein, human