DOCK8 is critical for the survival and function of NKT cells.
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.
Medical Research Council Human Immunology Unit, Weatherall Institute for Molecular Medicine, Oxford University, John Radcliffe Hospital, Oxford, United Kingdom;
Greg
G
Crawford
Anselm
A
Enders
Uzi
U
Gileadi
Sanda
S
Stankovic
Qian
Q
Zhang
Teresa
T
Lambe
Tanya L
TL
Crockford
Helen E
HE
Lockstone
Alexandra
A
Freeman
Peter D
PD
Arkwright
Joanne M
JM
Smart
Cindy S
CS
Ma
Stuart G
SG
Tangye
Christopher C
CC
Goodnow
Vincenzo
V
Cerundolo
Dale I
DI
Godfrey
Helen C
HC
Su
Katrina L
KL
Randall
Richard J
RJ
Cornall
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D016130:Immunophenotyping; D039001:Integrin alpha Chains / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D000950:Antigens, Ly; C516591:DOCK8 protein, human; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D018960:Hyaluronan Receptors; D039001:Integrin alpha Chains; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011948:Receptors, Antigen, T-Cell; C091367:alpha E integrins