title: Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse.
abstract: The immunological synapse formed by a T lymphocyte on the surface of a target cell contains a peripheral ring of filamentous actin (F-actin) that promotes adhesion and facilitates the directional secretion of cytokines and cytolytic factors. We show that growth and maintenance of this F-actin ring is dictated by the annular accumulation of phosphatidylinositol trisphosphate (PIP3) in the synaptic membrane. PIP3 functions in this context by recruiting the exchange factor Dock2 to the periphery of the synapse, where it drives actin polymerization through the Rho-family GTPase Rac. We also show that synaptic PIP3 is generated by class IA phosphoinositide 3-kinases that associate with T cell receptor microclusters and are activated by the GTPase Ras. Perturbations that inhibit or promote PIP3-dependent F-actin remodeling dramatically affect T cell cytotoxicity, demonstrating the functional importance of this pathway. These results reveal how T cells use lipid-based signaling to control synaptic architecture and modulate effector responses.
authors.affiliation: Immunology Program, 2 Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Floc'h
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Niels S
authors.initials: NS
authors.lastname: Bantilan
authors.forename: Guillaume
authors.initials: G
authors.lastname: Voisinne
authors.forename: Grégoire
authors.initials: G
authors.lastname: Altan-Bonnet
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
authors.forename: Morgan
authors.initials: M
authors.lastname: Huse
mesh_terms: D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D003602:Cytotoxicity, Immunologic; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D054992:Immunological Synapses / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D015398:Signal Transduction; D013570:Synaptic Membranes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D058534:Class I Phosphatidylinositol 3-Kinases; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D020744:rac GTP-Binding Proteins; C471356:DOCK2 protein, mouse; C510359:ELMO1 protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate; C421683:Pik3cd protein, mouse