Jennifer Bell

The natural killer (NK) cells of patients who have a defect in the NF- B pathway are not up to the job, according to a new study in The Journal of Clinical Investigation. But, the good news is that treatment with interleukin-2 (IL-2) can restore their killer potential.

Hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID) is an X-linked syndrome that results from mutations in the NEMO gene - which encodes inhibitor of B kinase- (IKK- ). IKK- is essential for the formation of a functional IKK complex, which phosphorylates I B ; this allows the translocation of NF- B to the nucleus and gene transcription. The immunodeficiency that is seen in patients with HED-ID is variable, but defects in both T- and B-cell responses have been reported.

Orange and colleagues studied three patients that had HED-ID; two of these were shown to have new mutations in NEMO. One of these patients had recurrent infections with cytomegalovirus (CMV), which is indicative of defective NK-cell activity. This led the authors to examine all three patients for NK-cell defects. The numbers of NK cells in the peripheral blood of these patients were within the normal range. However, the cytotoxic activity of the NK cells against tumour-cell targets in vitro - a classic measure of NK-cell function - was completely abolished. A control experiment showed that the patients' NK cells were effective in an antibody-dependent cellular cytotoxicity assay, which indicates that the cytotoxic effector machinery was intact.

Next, the authors investigated whether it might be possible to correct the NEMO-dependent NK-cell defect. In vitro treatment with IL-2, which is a potent enhancer of NK-cell activity, restored the cytotoxic activity of NK cells from patients with HED-ID. An electrophoretic mobility-shift assay then showed that stimulation with IL-2 induced NF- B activity in these NK cells. These in vitro findings provided the rationale for treating the patient who suffered from recurrent CMV infection with IL-2. Promisingly, ex vivo NK-cell cytotoxicity was apparent immediately and persisted for four weeks after treatment. So, in addition to defining a new molecular pathway in NK-cell activity, this study highlights a potential therapy to restore antiviral innate immunity in HED-ID patients.