Microbiology & Immunology - Research Publications

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Dock8 Regulates Lymphocyte Shape Integrity For Skin Antiviral Responses

Zhang, Q ; Dove, C ; Strauss-Albee, D ; Garcia, J ; Mandl, J ; Grodick, R ; Jing, H ; Chandler-Brown, D ; Kim, E ; Murdock, HM ; Crawford, GH ; Matthews, H ; Freeman, AF ; Cornall, R ; Germain, R ; Mueller, SN ; Su, H (SPRINGER/PLENUM PUBLISHERS, 2014-04)

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.