Deficient natural killer cell cytotoxicity in patients with IKK-γ/NEMO mutations

• Published in: The Journal of clinical investigation Vol. 109; no. 11; pp. 1501 - 1509
• Main Authors: Orange, Jordan S., Brodeur, Scott R., Jain, Ashish, Bonilla, Francisco A., Schneider, Lynda C., Kretschmer, Roberto, Nurko, Samuel, Rasmussen, Wendy L., Köhler, Julia R., Gellis, Stephen E., Ferguson, Betsy M., Strominger, Jack L., Zonana, Jonathan, Ramesh, Narayanaswamy, Ballas, Zuhair K., Geha, Raif S.
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.06.2002
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI14858

NF-κB essential modifier (NEMO), also known as IKK-γ, is a member of the I-κB kinase complex responsible for phosphorylating I-κB, allowing the release and activation of NF-κB. Boys with an expressed NEMO mutation have an X-linked syndrome characterized by hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID). The immunophenotype resulting from NEMO mutation is highly variable, with deficits in both T and B cell responses. We evaluated three patients with NEMO mutations (L153R, Q403X, and C417R) and HED-ID who had evidence of defective CD40 signaling. All three patients had normal percentages of peripheral blood NK cells, but impaired NK cell cytotoxic activity. This was not due to a generalized defect in cytotoxicity because antibody-dependent cellular cytotoxicity was intact. This abnormality was partially reversed by in vitro addition of IL-2, which was also able to induce NF-κB activation. In one patient with recurrent cytomegalovirus infections, administration of IL-2 partially corrected the NK cell killing deficit. These data suggest that NEMO participates in signaling pathways leading to NK cell cytotoxicity and that IL-2 can activate NF-κB and partially overcome the NK cell defect in patients with NEMO mutations.