Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity (#140)

Qian Zhang 1 , Jyh Liang Hor 2 , Christopher G Dove 1 , Heardly Murdock 1 , Dara Strauss-Albee 1 , Jordan Garcia 1 , Judith Mandl 3 , Devon Chandler-Brown 1 , Greg Crawford 4 , Richard J Cornall 4 , Ronald N Germain 3 , Scott N Mueller 2 , Helen c Su 1
  1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  2. The University of Melbourne, Parkville, VIC, Australia
  3. Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  4. MRC Human Immunology Unit, Nuffield Department of Medicine, Oxford University, , Oxford, UK

DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. Here 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 PAK, is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin tissue-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.