DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity
Zhang Q., Dove CG., Hor JL., Murdock HM., Strauss-Albee DM., Garcia JA., Mandl JN., Grodick RA., Jing H., Chandler-Brown DB., Lenardo TE., Crawford G., Matthews HF., Freeman AF., Cornall RJ., Germain RN., Mueller SN., Su HC.
<jats:p>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.</jats:p>