title: DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity.
abstract: DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Dove
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, and The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, and The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Jyh Liang
authors.initials: JL
authors.lastname: Hor
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Heardley M
authors.initials: HM
authors.lastname: Murdock
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Dara M
authors.initials: DM
authors.lastname: Strauss-Albee
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Garcia
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Mandl
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Grodick
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Huie
authors.initials: H
authors.lastname: Jing
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Devon B
authors.initials: DB
authors.lastname: Chandler-Brown
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Lenardo
authors.affiliation: MRC Human Immunology Unit, Nuffield Department of Medicine, Oxford University, Oxford OX3 7BN, England, UK.
authors.forename: Greg
authors.initials: G
authors.lastname: Crawford
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: MRC Human Immunology Unit, Nuffield Department of Medicine, Oxford University, Oxford OX3 7BN, England, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, and The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, and The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia hsu@niaid.nih.gov smue@unimelb.edu.au.
authors.forename: Scott N
authors.initials: SN
authors.lastname: Mueller
authors.affiliation: Laboratory of Host Defenses, Laboratory of Systems Biology, Laboratory of Immunology, and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 hsu@niaid.nih.gov smue@unimelb.edu.au.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D048430:Cell Shape / Q000187:drug effects / Q000276:immunology*; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; C516591:DOCK8 protein, human; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D003094:Collagen; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein