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

Research output: Contribution to journalArticle

62 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

Fingerprint

Antiviral Agents
Immunity
Lymphocytes
Skin
Cell Nucleus Shape
Confined Spaces
p21-Activated Kinases
T-Lymphocytes
Herpesviridae Infections
Chemotaxis
Natural Killer Cells
Cell Death
Collagen
Mutation
Infection

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., ... 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

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. / Zhang, Qian; Dove, Christopher G.; Hor, Jyh Liang; Murdock, Heardley M.; Strauss-Albee, Dara M.; Garcia, Jordan A.; Mandl, Judith N.; Grodick, Rachael A.; Jing, Huie; Chandler-Brown, Devon B.; Lenardo, Timothy E.; Crawford, Greg; Matthews, Helen F.; Freeman, Alexandra F.; Cornall, Richard J.; Germain, Ronald N.; Mueller, Scott N.; Su, Helen C.

In: Journal of Experimental Medicine, Vol. 211, No. 13, 2014, p. 2549-2566.

Research output: Contribution to journalArticle

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 2014, 'DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity', Journal of Experimental Medicine, vol. 211, no. 13, pp. 2549-2566. https://doi.org/10.1084/jem.20141307
Zhang, Qian ; Dove, Christopher G. ; Hor, Jyh Liang ; Murdock, Heardley M. ; Strauss-Albee, Dara M. ; Garcia, Jordan A. ; Mandl, Judith N. ; Grodick, Rachael A. ; Jing, Huie ; Chandler-Brown, Devon B. ; Lenardo, Timothy E. ; Crawford, Greg ; Matthews, Helen F. ; Freeman, Alexandra F. ; Cornall, Richard J. ; Germain, Ronald N. ; Mueller, Scott N. ; Su, Helen C. / DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. In: Journal of Experimental Medicine. 2014 ; Vol. 211, No. 13. pp. 2549-2566.
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