Immunodeficiency

Natural killers need NEMO

The natural killer (NK) cells of patients who have a defect in the NF-κB 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 κB kinase-γ (IKK-γ). IKK-γ is essential for the formation of a functional IKK complex, which phosphorylates IκBα; this allows the translocation of NF-κB 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-κB 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.

ORIGINAL RESEARCH PAPER

  1. 1

    Orange, J. S. et al. Deficient natural killer cell cytotoxicity in patients with IKK-γ/NEMO mutations. J. Clin. Invest. 109, 1501–1509 (2002)

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Bell, J. Natural killers need NEMO. Nat Rev Immunol 2, 463 (2002). https://doi.org/10.1038/nri851

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