DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity.

J Exp Med 2014 Dec 24;211(13):2549-66. Epub 2014 Nov 24.

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

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.

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http://dx.doi.org/10.1084/jem.20141307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267229PMC
December 2014

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