NFKB1 regulates human NK cell maturation and effector functions

- NK cells from patients with NFKB1 mutations show impaired peripheral maturation.
- NK cells from NFKB1 mutated patients show profound defects in key effector functions, ie cytotoxicity and IFN-γ production.
- NFKB1 mutated NK cells show a trend towards impaired IL-2 induced proliferation and NKp44 up-regulation.
- NFKB1 haploinsufficient patients show a high prevalence of viral infections.

NFKB1, a component of the canonical NF-κB pathway, was recently reported to be mutated in a limited number of CVID patients. CVID-associated mutations in NFKB2 (non-canonical pathway) have previously been shown to impair NK cell cytotoxic activity. Although a biological function of NFKB1 in non-human NK cells has been reported, the role of NFKB1 mutations for human NK cell biology and disease has not been investigated yet. We decided therefore to evaluate the role of monoallelic NFKB1 mutations in human NK cell maturation and functions. We show that NFKB1 mutated NK cells present impaired maturation, defective cytotoxicity and reduced IFN-γ production upon in vitro stimulation. Furthermore, human IL-2 activated NFKB1 mutated NK cells fail to up-regulate the expression of the activating marker NKp44 and show reduced proliferative capacity. These data suggest that NFKB1 plays an essential novel role for human NK cell maturation and effector functions.