title: Cytotoxic T Cells Use Mechanical Force to Potentiate Target Cell Killing.
abstract: The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting mechanical force. Here, we investigated whether synaptic forces promote the destruction of target cells. CTLs kill by secreting toxic proteases and the pore forming protein perforin into the synapse. Biophysical experiments revealed a striking correlation between the magnitude of force exertion across the synapse and the speed of perforin pore formation on the target cell, implying that force potentiates cytotoxicity by enhancing perforin activity. Consistent with this interpretation, we found that increasing target cell tension augmented pore formation by perforin and killing by CTLs. Our data also indicate that CTLs coordinate perforin release and force exertion in space and time. These results reveal an unappreciated physical dimension to lymphocyte function and demonstrate that cells use mechanical forces to control the activity of outgoing chemical signals.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Roshni
authors.initials: R
authors.lastname: Basu
authors.affiliation: Biochemistry and Molecular Biology Graduate Program, Weill-Cornell Medical College, New York, NY 10065, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Whitlock
authors.affiliation: Hydrodynamics Laboratory (LadHyX), Department of Mechanics, Ecole Polytechnique, Palaiseau 91128, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Husson
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Floc'h
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
authors.forename: Weiyang
authors.initials: W
authors.lastname: Jin
authors.affiliation: Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Oyler-Yaniv
authors.affiliation: Program in Cellular and Molecular Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Farokh
authors.initials: F
authors.lastname: Dotiwala
authors.affiliation: CNRS, University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux 33000, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Giannone
authors.affiliation: Institute Curie, INSERM U932, PSL Research University, Paris 75005, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Hivroz
authors.affiliation: Department of Biology, Brooklyn College of the City University of New York, New York, NY 11201, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Biais
authors.affiliation: Program in Cellular and Molecular Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
authors.forename: Lance C
authors.initials: LC
authors.lastname: Kam
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: husem@mskcc.org.
authors.forename: Morgan
authors.initials: M
authors.lastname: Huse
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D054992:Immunological Synapses; D051379:Mice; D054353:Perforin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000502:physiology*
chemical_list: D054353:Perforin; D019869:Phosphatidylinositol 3-Kinases