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.This work was supported by the Medical Research Council, National Institute for Health Research Biomedical Research Centre Program, National Institutes of Medical Research, Australian National Health and Medical Research Council (NHMRC), and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The authors acknowledge the following personal awards: Medical Research Council Centenary Early Career Award (to G.C.), NHMRC Career Development Fellowship (to A.E.), NHMRC Senior Principal Research Fellowship (to D.I.G.), NHMRC Career Development Fellowship (to C.S.M.), NHMRC grant GNT1022922 (to K.L.R.), and NHMRC Principal Research Fellowship (to S.G.T.)