Comments for:
Abstract
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.
Authors
Jordan S. Orange, Scott R. Brodeur, Ashish Jain, Francisco A. Bonilla, Lynda C. Schneider, Roberto Kretschmer, Samuel Nurko, Wendy L. Rasmussen, Julia R. Köhler, Stephen E. Gellis, Betsy M. Ferguson, Jack L. Strominger, Jonathan Zonana, Narayanaswamy Ramesh, Zuhair K. Ballas, Raif S. Geha
Impaired natural cytotoxicity but preserved ADCC: TAP-deficient NK cells also have it
Submitter: Jacques Zimmer | Jacques.Zimmer@isrec.unil.ch
INSERM EP 99-08/Etabliss. Français du Sang-Alsace/10 rue Spielmann/F-67065 Strasbourg Cedex/France
Published August 20, 2002
We read with interest the article of Orange et al. (1) in a recent issue of the journal. The results shown in this work suggest that NK cells from patients with IKK-g/NEMO mutations have a defective natural cytotoxicity but retain ADCC. This is obviously an important finding, because it implicates NEMO and NF-kB in the regulation of NK cell cytotoxic functions.
In their discussion, the authors claim that "humans with phenotypically normal NK cells capable of mediating ADCC but lacking NK cell cytotoxicity have never been described". However, we described the same pattern of impaired natural cytotoxicity but preserved ADCC in NK cells from TAP-deficient patients (2). TAP (transporter associated to antigen processing) is a peptide transporter which is crucial for the import of cytosolic peptides into the lumen of the endoplasmic reticulum (3). In TAP-deficiency, newly synthesized HLA class I molecules are poorly loaded with peptides, remain unstable, and their surface expression is very low (1 - 3 % of normal) (2). As NK cells preferentially kill cells with low or absent HLA class I expression, they could be potentially autoreactive in these patients. However, their peripheral blood NK cells are completely devoid of cytotoxic activity towards K562 cells (also used as targets by Orange et al.) as well as autologous EBV-transformed B cells (2). In contrast, ADCC against antibody -coated targets is maintained (2). Thus, resting TAP-deficient NK cells seem to behave exactly as NK cells from patients with IKK-g/NEMO mutations. Likewise, their defective natural cytotoxicity is restored after culture in IL-2 (2).
The authors consider that the NK cells of their patients had a normal phenotype. This phenotype is not further described however, in particular regarding the expression of various adhesion molecules (CD2, CD11, CD62L), as well as activating (NCR, NKG2D, 2B4?) or inhibitory receptors (KIR, ILT2, CD94/NKG2A) that are crucial for the regulation of cytotoxic NK cell functions (4). We found, after detailed analysis, that the overall marker expression phenotype is normalin TAP-deficient patients' NK cells (2, 5).
References
1.Orange, J.S., S.R. Brodeur, A. Jain, F.A. Bonilla, L.C. Schneider, R. Kretschmer, S. Nurko, W.L. Rasmussen, J.R. Köhler, S.E. Gellis, B.M. Ferguson, J.L. Strominger, J. Zonana, N. Ramesh, Z.K. Ballas, and R.S. Geha. 2002. Deficient natural killer cell cytotoxicity in patients with IKK-g/NEMO mutations. J. Clin. Invest. 109:1501-1509.
2.Zimmer, J., L. Donato, D. Hanau, J.P. Cazenave, M.M. Tongio, A. Moretta, and H. de la Salle. 1998. Activity and phenotype of natural killer cells in peptide transporter (TAP)-deficient patients (type I bare lymphocyte syndrome). J. Exp. Med. 187:117-22.
3.York, I.A., and K.L. Rock. 1996. Antigen processing and presentation by the class I major histocompatibility complex. Annu Rev Immunol 14:369-396.
4.Moretta, A., C. Bottino, M.C. Mingari, R. Biassoni, and L. Moretta. 2002. What is a natural killer cell? Nature Immunol. 3:6-8.
5.Vitale, M., J. Zimmer, R. Castriconi, D. Hanau, L. Donato, C. Bottino, L. Moretta, H. de la Salle, and A. Moretta. 2002. Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells. Blood 99:1723- 1729.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)