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J Exp Med. 2014 Dec 15;211(13):2549-66. doi: 10.1084/jem.20141307. Epub 2014 Nov 24.

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity.

Author information

1
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.
2
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.
3
MRC Human Immunology Unit, Nuffield Department of Medicine, Oxford University, Oxford OX3 7BN, England, UK.
4
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.
5
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.

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.

PMID:
25422492
PMCID:
PMC4267229
DOI:
10.1084/jem.20141307
[Indexed for MEDLINE]
Free PMC Article

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