The low cytotoxic activity of peripheral blood NK cells may relate to unexplained recurrent miscarriage

Unexplained recurrent miscarriage (uRM) is defined as two or more spontaneous abortions prior to 20 weeks of gestation with unknown etiology. Peripheral blood natural killer (pNK) cells contact with the villus and exert important role in normal pregnancy. However, it is still controversial about the association between pNK cytotoxicity and uRM, and the underlying mechanism remains unknown so far.

In this study, we aim to compare the percentage, immunophenotype, and function of pNK cells between patients with uRM and fertile controls. The peripheral blood was collected from 49 patients with uRM and 11 fertile women in their middle luteal phase of the menstrual cycle. pNK cells were co-cultured with K562 cells at different cell ratios to measure the cytotoxicity. The percentage of CD3^- CD56⁺ , CD3^- CD56^bright , and CD3^- CD56^dim pNK was analyzed by flow cytometry and quantified to evaluate the expression of cytotoxic granules (granzyme B, granulysin, and perforin), and the cell surface receptors related to pNK cell cytotoxicity (NKG2D, NKp30, NKp46, CD158a, and CD158b) were also detected.

The general linear model analysis showed that pNK cell cytotoxicity in patients with uRM was significantly lower than that in fertile controls. In addition, the ratios of NKG2D/CD158a, NKp30/CD158a, and NKp46/CD158a in CD3^- CD56^bright pNK subsets were significantly lower in uRM group than that in fertile control. The logistical regression analysis showed that the reduced NKp30/CD158a, NKp46/CD158a ratios in CD3^- CD56^bright pNK subsets were significantly associated with uRM.

Our results suggested that a low pNK cytotoxicity, which is mediated by inhibitory signals, might be associated with uRM.