NFKB1 regulates human NK cell maturation and effector functions

Abstract

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 upregulate 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.

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

“…Both P2 and P3 presented with autoimmune cytopaenias and although both currently in remission, knowledge of the underlying genetic cause has meant that their immunosuppression with mycophenolate mofetil (MMF) should not be withdrawn due to high risk of disease relapse. Patients with NFKB1 haploinsufficiency suffer with EBV reactivation and disease due to intrinsic natural killer cell defects . From the clinical and immunological phenotypes of P2 and P3, we would not have expected this, but now with knowledge of the monogenic PID cause we will continually monitor EBV viral loads due to lymphoma risk …”

“…NFKB1 haploinsufficiency is described to cause a wide range of autoimmune/inflammatory diseases. 42 52 From the clinical and immunological phenotypes of P2 and P3, we would not have expected this, but now with knowledge of the monogenic PID cause we will continually monitor EBV viral loads due to lymphoma risk. 43 In P16 and P20, pathogenic CTLA4 missense variants cause immunodeficiency with multi-system autoimmunity due to impaired regulatory T cell function.…”

Interaction between piperine and genes associated with sciatica and its mechanism based on molecular docking technology and network pharmacology

“…NF-kB1 is a protein factor that can specifically bind to the enhancer KB sequence of immunoglobulin K light chain gene [46]. It can specifically bind to a variety of cell gene promoters or enhancer sequence-specific sites to promote transcription and expression, and participate in inflammatory response, immune response, cell proliferation, transformation and apoptosis and other important pathophysiological processes [47]. In the process of inflammation, NF-kB enters the nucleus after being activated, which has a strong ability to bind to the NF-kB1 gene site, and is the premise and key of transcription and release of cytokines.…”

Proteomic and transcriptomic studies of HBV-associated liver fibrosis of an AAV-HBV-infected mouse model

“…The expression level of Traf3 is decreased in chronic HBV-infected patients, and this protein can interact with the HBX protein [ 37 ]. Nfkb1 can regulate human NK cell maturation and effector functions [ 38 , 39 ]. These results suggest that in the course of HBV infection, the host itself regulates the activity of the RIG pathway through Ankrd17 to enhance the immune response, but the HBx protein may inhibit this effect.…”