CARD11 dominant negative mutation leads to altered human Natural Killer cell homeostasis

Dominant negative mutations in CARD11 have been reported in patients with immune dysregulation, severe atopic features, and variable T cell alterations. Data on Natural killer (NK) cells from affected patients are lacking. We report on a 12-year-old boy with severe atopic dermatitis, food induced anaphylaxis and hypogammaglobulinemia harbouring a novel de novo heterozygous variant c.169G > A; p.Glu57Lys in CARD11. The dominant negative effect of this mutation was confirmed on both CD4⁺ and CD8⁺. CTLA4⁺Foxp3⁺CD4⁺ Tregs were severely reduced. Patient's NK cells showed reduced expression of NKp46, NKG2D and CD69. Patient's CD56^bright NK cells showed in vitro impaired production of IFN-γ. Steady state pS6 levels on patient's NK cells were increased and remained elevated upon IL2 + IL12 + IL18 overnight stimulation. Overall, the effect of CARD11 mutation on mTORC1 differs between T and NK cells. These findings may explain the increased susceptibility to viral infections and the reduced immune surveillance in affected patients.