Gestational stage and fetal allogeneity shape cytokine and cytokine receptor isoform expression in the murine placenta

Abstract

Abstract Pregnancy requires the maternal immune system to tolerate a semi-allogeneic fetus while preserving the capacity to respond to infection, yet how alternative transcript isoforms contribute to immune regulation at the maternal–fetal interface remains poorly understood. Here, we applied full-length single-cell RNA sequencing to murine placentas from syngeneic and semi-allogeneic pregnancies at mid- (E12.5) and late (E19.5) gestation. Semi-allogeneic placentas at E12.5 exhibited broad suppression of cytokine and chemokine gene expression, whereas syngeneic placentas at E12.5 and both pregnancy types at E19.5 displayed a shared pro-inflammatory transcriptional program. This transition was accompanied by coordinated expression of alternatively spliced cytokine receptor isoforms alongside their canonical counterparts rather than by isoform switching. Predicted protein products of these alternative isoforms frequently lacked transmembrane domains, intracellular signaling regions, or signal peptides, consistent with a potential role in modulating cytokine responsiveness. We additionally identified three transcriptionally distinct maternal erythroid populations expressing NK-, antigen-presenting-cell-, and neutrophil-associated gene signatures, consistent with a broader role for placental erythroid cells in immune regulation. Together, these findings provide an isoform-resolved view of immune regulation during murine pregnancy, identify gestation- and pregnancy type-associated cytokine receptor isoforms, and nominate immune-like erythroid populations as candidate contributors to immune homeostasis at the maternal–fetal interface.