Journal of Experimental Medicine 2014-12-15

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity.

Qian Zhang, Christopher G Dove, Jyh Liang Hor, Heardley M Murdock, Dara M Strauss-Albee, Jordan A Garcia, Judith N Mandl, Rachael A Grodick, Huie Jing, Devon B Chandler-Brown, Timothy E Lenardo, Greg Crawford, Helen F Matthews, Alexandra F Freeman, Richard J Cornall, Ronald N Germain, Scott N Mueller, Helen C Su

Index: J. Exp. Med. 211(13) , 2549-66, (2014)

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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.