Induction of Membrane Ceramides: A Novel Strategy to Interfere with T Lymphocyte Cytoskeletal Reorganisation in Viral Immunosuppression

PLoS Pathogens

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