The maternal immune response at conception sets the trajectory for pregnancy success. Tolerance mediated by regulatory T cells (Treg cells) towards paternally-inherited major and minor histocompatibility complex antigens (MHC and MiHC) expressed by placental and fetal cells is essential. However, the relative contributions of MHC and MiHC genes for improved pregnancy outcomes and their significance for offspring phenotype is unknown.
C57BL/6 female mice were mated with C57BL/6 (MHC&MiHC-matched), Balb/b (MHC-matched, MiHC-disparate) and Balb/c (MHC&MiHC-disparate) males, and pregnancy outcomes were evaluated on gestational day (gd) 17.5 (n=15-17 dams/group). In another cohort, offspring growth trajectories were measured and metabolic health was evaluated by glucose tolerance test in adulthood (n=3-7 dams/group).
On gd17.5, pregnancies sired by Balb/b and Balb/c showed reduced fetal loss compared to C57BL/6 males (p<0.01). Although fetal and placental weights were higher in Balb/b and Balb/c matings compared to C57BL/6 mating (p<0.001), the fetal-to-placental weight ratio was 11% lower after Balb/b than Balb/c mating and histological analysis of mid-sagittal placental sections revealed a larger placental labyrinth zone (p<0.05), indicative of reduced placental efficiency, when parental MHC was not disparate.
Postnatally, both male and female offspring of Balb/b and Balb/c sires were heavier than C57BL/6 sires from weaning until week 20 postpartum (pp; p<0.001), and exhibited improved glucose tolerance (area under curve, p<0.0001). Female offspring from Balb/b sires weighed more after week 5pp and were less glucose tolerant than Balb/c offspring (p<0.0001).
Our findings demonstrate that disparity in both MHC and MiHC between parents maximises pregnancy outcomes by inducing robust placentation with long-term benefits for offspring metabolic health, particularly in female offspring. We conclude that disparity between parental MHC and MiHC is critical for efficient female reproductive investment and offspring growth trajectory and metabolic health after birth.