PLoS Pathogens | |
Induction of Membrane Ceramides: A Novel Strategy to Interfere with T Lymphocyte Cytoskeletal Reorganisation in Viral Immunosuppression | |
Erich Gulbins1  Georg Krohne2  Sibylle Schneider-Schaulies3  Evelyn Gassert3  Harry Harms3  Elita Avota3  | |
[1] Department for Molecular Biology, University of Essen, Essen, Germany;Department of Electron Microscopy, University of Würzburg, Würzburg, Germany;Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany | |
关键词: T cells; Cell membranes; Cytoskeleton; Measles virus; Actins; Cell motility; Membrane receptor signaling; T cell receptors; | |
DOI : 10.1371/journal.ppat.1000623 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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 β1 integrin ligation or αCD3/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.
【 授权许可】
CC BY
【 预 览 】
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