DOCK8 is critical for the survival and function of NKT cells.

Greg Crawford, Anselm Enders, Uzi Gileadi, Sanda Stankovic, Qian Zhang, Teresa Lambe, Tanya L. Crockford, Helen E. Lockstone, Alexandra Freeman, Peter D. Arkwright, Joanne M. Smart, Cindy S. Ma, Stuart G. Tangye, Christopher C. Goodnow, Vincenzo Cerundolo, Dale I. Godfrey, Helen C. Su, Katrina L. Randall, Richard J. Cornall

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper-immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8-deficient mice lack a terminally differentiated subset of NK1.1(+) NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease.

Original languageEnglish
Pages (from-to)2052-2061
Number of pages10
JournalBlood
Volume122
Issue number12
DOIs
Publication statusPublished - 19 Sep 2013
Externally publishedYes

Fingerprint

Natural Killer T-Cells
Cytokinesis
T-cells
Survival
Integrins
Cell Count
Thymus
Lymphocyte Function-Associated Antigen-1
Eczema
B-Cell Lymphoma
Virus Diseases
Liver
Immunoglobulin E
Bacterial Infections
Thymus Gland
Cells
Cytokines
Antigens
Defects

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Crawford, G., Enders, A., Gileadi, U., Stankovic, S., Zhang, Q., Lambe, T., ... Cornall, R. J. (2013). DOCK8 is critical for the survival and function of NKT cells. Blood, 122(12), 2052-2061. https://doi.org/10.1182/blood-2013-02-482331

DOCK8 is critical for the survival and function of NKT cells. / Crawford, Greg; Enders, Anselm; Gileadi, Uzi; Stankovic, Sanda; Zhang, Qian; Lambe, Teresa; Crockford, Tanya L.; Lockstone, Helen E.; Freeman, Alexandra; Arkwright, Peter D.; Smart, Joanne M.; Ma, Cindy S.; Tangye, Stuart G.; Goodnow, Christopher C.; Cerundolo, Vincenzo; Godfrey, Dale I.; Su, Helen C.; Randall, Katrina L.; Cornall, Richard J.

In: Blood, Vol. 122, No. 12, 19.09.2013, p. 2052-2061.

Research output: Contribution to journalArticle

Crawford, G, Enders, A, Gileadi, U, Stankovic, S, Zhang, Q, Lambe, T, Crockford, TL, Lockstone, HE, Freeman, A, Arkwright, PD, Smart, JM, Ma, CS, Tangye, SG, Goodnow, CC, Cerundolo, V, Godfrey, DI, Su, HC, Randall, KL & Cornall, RJ 2013, 'DOCK8 is critical for the survival and function of NKT cells.', Blood, vol. 122, no. 12, pp. 2052-2061. https://doi.org/10.1182/blood-2013-02-482331
Crawford G, Enders A, Gileadi U, Stankovic S, Zhang Q, Lambe T et al. DOCK8 is critical for the survival and function of NKT cells. Blood. 2013 Sep 19;122(12):2052-2061. https://doi.org/10.1182/blood-2013-02-482331
Crawford, Greg ; Enders, Anselm ; Gileadi, Uzi ; Stankovic, Sanda ; Zhang, Qian ; Lambe, Teresa ; Crockford, Tanya L. ; Lockstone, Helen E. ; Freeman, Alexandra ; Arkwright, Peter D. ; Smart, Joanne M. ; Ma, Cindy S. ; Tangye, Stuart G. ; Goodnow, Christopher C. ; Cerundolo, Vincenzo ; Godfrey, Dale I. ; Su, Helen C. ; Randall, Katrina L. ; Cornall, Richard J. / DOCK8 is critical for the survival and function of NKT cells. In: Blood. 2013 ; Vol. 122, No. 12. pp. 2052-2061.
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AU - Lambe, Teresa

AU - Crockford, Tanya L.

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AU - Ma, Cindy S.

AU - Tangye, Stuart G.

AU - Goodnow, Christopher C.

AU - Cerundolo, Vincenzo

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