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

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68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2549-2566
Number of pages18
JournalJournal of Experimental Medicine
Volume211
Issue number13
DOIs
Publication statusPublished - 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Zhang, Q., Dove, C. G., Hor, J. L., Murdock, H. M., Strauss-Albee, D. M., Garcia, J. A., Mandl, J. N., Grodick, R. A., Jing, H., Chandler-Brown, D. B., Lenardo, T. E., Crawford, G., Matthews, H. F., Freeman, A. F., Cornall, R. J., Germain, R. N., Mueller, S. N., & Su, H. C. (2014). DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. Journal of Experimental Medicine, 211(13), 2549-2566. https://doi.org/10.1084/jem.20141307