title: The strength of T cell receptor signal controls the polarization of cytotoxic machinery to the immunological synapse.
abstract: Killing by cytotoxic T lymphocytes (CTLs) is mediated by the secretion of lytic granules. The centrosome plays a key role in granule delivery, polarizing to the central supramolecular activation complex (cSMAC) within the immunological synapse upon T cell receptor (TCR) activation. Although stronger TCR signals lead to increased target cell death than do weaker signals, it is not known how the strength of TCR signal controls polarization of the centrosome and lytic granules. By using TCR transgenic OT-I CTLs, we showed that both high- and low-avidity interactions led to centrosome polarization to the cSMAC. However, only high-avidity interactions, which induced a higher threshold of intracellular signaling, gave rise to granule recruitment to the polarized centrosome at the synapse. By controlling centrosome and granule polarization independently, the centrosome is able to respond rapidly to weak signals so that CTLs are poised and ready for the trigger for granule delivery.
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Misty R
authors.initials: MR
authors.lastname: Jenkins
authors.forename: Andy
authors.initials: A
authors.lastname: Tsun
authors.forename: Jane C
authors.initials: JC
authors.lastname: Stinchcombe
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology*; D018385:Centrosome / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005260:Female; D054992:Immunological Synapses / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: C110366:OVA-8; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases