Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

Abstract

Patients with recurrent miscarriage (RM) show up-regulated cytotoxic natural killer (NK) cells that are suspected to play a causal role in abortion. In the present study, we investigated counter-regulating inhibitory mechanisms and compared the results in RM patients with those of healthy controls (HC), patients with end-stage renal disease (ESRD) and kidney transplant recipients late post-transplant (TX). NK, NK T and T cell subsets were analysed in the peripheral blood of 31 RM, 14 female ESRD and nine female TX patients as well as 21 female HC using eight-colour fluorescence flow cytometry. Compared with HC, RM patients showed significantly higher absolute numbers of CD56⁺ NK cells co-expressing the phenotype interferon (IFN)-γR⁺ , IL-4⁺ , transforming growth factor (TGF)-β⁺ , IL-4⁺ human leucocyte antigen D-related (HLA-DR)⁺ , TGF-β⁺ HLA-DR⁺ , IL-4⁺ TGF-β⁺ , IL-4⁺ TGF-β^- , IFN-γ⁺ and/or IL-10^- IFN-γ⁺ (all P ≤ 0·01), more IL-17⁺ CD56^bright (P = 0·028) NK cells and more CD56^dim CD16⁺ NK cells co-expressing IFN-γR, IFN-γ, IL-4 and/or TGF-β (all P ≤ 0·01). When the same cell subsets were analysed in ESRD or TX patients, cytokine-producing NK cell subsets were not significantly different from those of HC. RM patients showed significantly higher absolute numbers of CD158a⁺ , CD158b⁺ , CD158a^- CD158e⁺ (all P < 0·05), NKG2D⁺ NKG2A⁺ , NKG2D ⁺ NKG2A^- , NKG2D⁺ and/or NKG2A⁺ (all P ≤ 0·01) CD56⁺ NK cells and higher CD158a⁺ , CD158b⁺ (all P < 0·05), NKG2D⁺ and/or NKG2A⁺ (all P < 0·01) CD56^dim+ CD16⁺ NK cells than HC. In contrast, ESRD patients had normal and TX recipients had lower CD158a⁺ and NKG2D⁺ NKG2A^- CD56⁺ NK cells and lower CD158a⁺ CD56^dim+ CD16⁺ NK cells (all P < 0·05) than HC. RM patients have abnormally high circulating NK cells expressing inhibitory cytokines and inhibitory surface receptors which might contribute to the pathogenesis of RM.

Keywords: NK cell subsets; inhibitory cytokines; inhibitory surface receptors; kidney transplant recipients late post-transplant; patients with recurrent miscarriage.