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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.

Original publication

DOI

10.1084/jem.20141307

Type

Journal article

Journal

J Exp Med

Publication Date

15/12/2014

Volume

211

Pages

2549 - 2566

Keywords

Animals, Apoptosis, Cattle, Cell Adhesion, Cell Nucleus, Cell Shape, Chemokine CXCL12, Chemotaxis, Collagen, Cytoskeleton, Female, Guanine Nucleotide Exchange Factors, Humans, Immunity, Immunologic Memory, Killer Cells, Natural, Male, Mice, Mice, Inbred C57BL, Signal Transduction, Skin, T-Lymphocytes, cdc42 GTP-Binding Protein, p21-Activated Kinases