RESUMO
The Fas/CD95 surface receptor mediates rapid death of various cell types, including autoreactive T cells with the potential for triggering autoimmunity. Here, we present novel aspects of Fas signalling that define a 'social' dimension to receptor-induced apoptosis. Fas stimulation rapidly induces extensive membrane nanotube formation between neighbouring T cells. This is critically dependent on Rho GTPases but not on caspase activation. Bidirectional transfer of membrane and cytosolic elements including active caspases can be observed to occur via these nanotubes. Nanotube formation and intercellular exchanges of death signals are defective in T lymphocytes from patients with autoimmune lymphoproliferative syndrome harbouring mutations in the Fas receptor. We conclude that nanotube-mediated exchanges constitute a novel form of intercellular communication that augments the propagation of death signalling between neighbouring T cells.
Assuntos
Apoptose/fisiologia , Comunicação Celular/fisiologia , Extensões da Superfície Celular/imunologia , Extensões da Superfície Celular/ultraestrutura , Nanotubos de Peptídeos/ultraestrutura , Transdução de Sinais/fisiologia , Linfócitos T/ultraestrutura , Receptor fas/metabolismo , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Síndrome Linfoproliferativa Autoimune/fisiopatologia , Caspases/metabolismo , Linhagem Celular , Células Cultivadas , Espaço Extracelular/metabolismo , Imunofluorescência , Humanos , Células Jurkat , Microscopia Eletrônica de Transmissão , Transporte Proteico/fisiologia , Linfócitos T/imunologia , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
The death receptor Fas/CD95 initiates apoptosis by engaging diverse cellular organelles including endosomes. The link between Fas signaling and membrane traffic has remained unclear, in part because it may differ in diverse cell types. After a systematic investigation of all known pathways of endocytosis, we have clarified that Fas activation opens clathrin-independent portals in mature T cells. These portals drive rapid internalization of surface proteins such as CD59 and depend upon actin-regulating Rho GTPases, especially CDC42. Fas-enhanced membrane traffic invariably produces an accumulation of endocytic membranes around the Golgi apparatus, in which recycling endosomes concentrate. This peri-Golgi polarization has been documented by colocalization analysis of various membrane markers and applies also to active caspases associated with internalized receptor complexes. Hence, T lymphocytes show a diversion in the traffic of endocytic membranes after Fas stimulation that seems to resemble the polarization of membrane traffic after their activation.
