期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 13, 页码 2549-2566出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20141307
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资金
- Intramural Research Program of the NIAID
- NIH
- Australian Research Council
- Medical Research Council UK
- Oxford NIHR Biomedical Research Centre
- MRC [MC_UU_12010/6] Funding Source: UKRI
- Medical Research Council [MC_UU_12010/6] Funding Source: researchfish
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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