Human leucocyte antigen G (HLA-G) and its murine homologue Qa-2 protect from pregnancy loss

Abstract During pregnancy, the maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. The MHC-Ib molecule HLA-G is well known to mediate immunological tolerance. However, no in-vivo studies have yet demonstrated a beneficial role of HLA-G for pregnancy success. Myeloid derived suppressor cells (MDSC) are suppressively acting immune cells accumulating during pregnancy and mediating maternal-fetal tolerance. Here, we analyzed the impact of Qa-2, the murine homologue to HLA-G, on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by changes in uterine gene expression, altered spiral artery remodeling and protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused decreased accumulation of MDSC and impaired MDSC function. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for the treatment of immunological pregnancy complications.