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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cattle
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Cell Adhesion / drug effects
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Cell Nucleus / drug effects
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Cell Nucleus / pathology
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Cell Shape / drug effects
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Cell Shape / immunology*
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Chemokine CXCL12 / pharmacology
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Chemotaxis / drug effects
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Collagen / pharmacology
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Cytoskeleton / drug effects
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Cytoskeleton / metabolism
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Female
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Guanine Nucleotide Exchange Factors / deficiency
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Guanine Nucleotide Exchange Factors / metabolism*
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Humans
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Immunity* / drug effects
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Immunologic Memory / drug effects
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Killer Cells, Natural / pathology*
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Male
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Mice
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Mice, Inbred C57BL
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Signal Transduction / drug effects
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Skin / drug effects
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Skin / immunology*
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Skin / pathology
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Skin / virology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology*
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cdc42 GTP-Binding Protein / metabolism
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p21-Activated Kinases / metabolism
Substances
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Chemokine CXCL12
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DOCK8 protein, human
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Dock8 protein, mouse
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Guanine Nucleotide Exchange Factors
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Collagen
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p21-Activated Kinases
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cdc42 GTP-Binding Protein