Effects of homo‐ and heterozygous TREM2 mutations on natural killer cell activity

Abstract

AbstractBackgroundNasu‐Hakola disease (NHD) is a rare genetic neurodegenerative disorder characterised by progressive presenile dementia and bone cysts. Dysfunctions in myeloid‐derived innate immune cells such as microglia due to loss‐of‐function mutations in the TREM2 (trigger receptor 2 expressed on myeloid cells) gene cause the clinical manifestations. Heterozygous carriers have strongly increased risk of developing Alzheimer’s Disease but do not present with NHD symptoms. TREM2 is associated with DAP12 protein, which contains an immunoreceptor tyrosine‐based activation motif that is structurally similar to natural killer (NK) cell receptors. In this study, we aimed to analyse the effects of TREM2 mutation and its effect on the peripheral immune system represented by NK cell functions.MethodSix patients with NHD with a defined homozygous TREM2 mutation, 7 carriers with heterozygous TREM2 mutations and 10 age‐ and gender‐matched controls were included. NK cell subsets, KIR expressions (NKG2A, NKG2D, NKp46), cytotoxic activity (CD107a, Perforin, Granzyme A) and cytokine secretions (IL‐4, IFN‐γ, TNF‐α, IL‐10, IL‐17, TGF‐β) were analysed by flow cytometry.ResultCD3−CD56dimCD16− (p = 0.003) subsets were found to be increased in the NHD group compared to carriers. Activating C‐type lectin receptor NKG2D expression was increased in CD8+ (p = 0.003) NK cell subsets in the NHD group. Inhibiting C‐type lectin receptor NKG2A expression was increased in total (p = 0.011) as well as CD8+ (p = 0.007) NK cell subsets in carriers compared to controls. In total NK cells, intracellular TNF‐α (p = 0.005) and TGF‐β (p = 0.013) levels were decreased, IL‐17 (p = 0.05) and IL‐4 (p = 0.005) levels were increased in the NHD group. When NK cells were grouped due to their CD8 expression, TNF‐α levels were decreased, and IL‐17 levels were increased in both subsets in the NHD group. Cytotoxic activity showed no differentiation in both unstimulated and K562 stimulated conditions between groups.ConclusionUnlike previous case series, NK cell ratios did not differ between groups. Over‐expression of inhibiting receptors in the carriers group, unlike high levels of activating receptors in the NHD, might explain the lack of symptoms in the carriers. The increased ratio of CD3−CD56dimCD16− NK cell subsets that overexpress inhibitory checkpoints might explain the low levels of pro‐inflammatory cytokines in the NHD group.