Targeting CD49a+PBX1+ NK cells in recurrent spontaneous abortion immunotherapy

Abstract Objective In the first trimester, CD49a+ natural killer (NK) cells are the main immune cells at the maternal-fetal interface. We have demonstrated that uterine NK cells have important physiological functions that can secrete various growth factors to promote fetal development. However, the functional subsets and transcriptional regulation mechanisms of NK cells expressing GPFs are unclear. Result Here, we have identified CD49a+PBX1+ NK cells as a unique subset in which the transcription factor, PBX1, upregulates the expression of the GPFs, pleiotrophin and osteoglycin, to promote fetal development at the maternal-fetal interface of both humans and mice. The results of ChIP experiments with anti-PBX1 antibody in decidual NK cells shown that PBX1 regulates the transcription of pleiotrophin and osteoglycin genes via direct binding. Inactivation of Pbx1 in mouse NK cells caused impaired fetal development due to a significantly decrease in the expression of GPFs. The results of exome sequencing of decidual NK cells from patients with unexplained recurrent spontaneous abortion (URSA), revealed decreased expression of PBX1 correlated with fetal growth restriction and pregnancy failure, suggesting that the impaired PBX1 gene in decidual NK cells is a potential biomarker for URSA. Conclusion Our study revealed that the transcriptional regulation mechanism in NK cells at the maternal-fetal interface, and suggested that impaired CD49a+PBX1+ NK cells contribute to the etiology of URSA, and provided the basis for improved approaches to NK cell-based immunotherapy for pregnancy related diseases.