Dysfunctional decidual CD2(+)CD4(+)T cells regulated by Rev-erbα - GFPT1 - GPI anchored CD58 axis of decidual stromal cells underlies sleep disturbance induced recurrent pregnancy loss.

BACKGROUND: The multifactorial nature of recurrent pregnancy loss (RPL) requires a comprehensive understanding of its diverse risk factors, including sleep disturbance. Previously, we reported decreased Rev-erbα expression in decidual stromal cells from pregnant mice with sleep disturbance (SD) and patients of RPL with sleep disturbance (RS). METHODS: Omics analyses were used to predict the interaction between Rev-erbα and glutamine-fructose-6-phosphate amidotransferase 1 (GFPT1). Tunicamycin and peptide-N-glycosidase F and phosphatidylinositol-specific phospholipase C treatment were conducted to analyze the glycosylation modification type of CD58. The coculture between decidual immune cells and decidual stroma cells (DSCs) in which Rev-erbα, GFPT1, or CD58 was either knockdown or overexpressed was performed to evaluate the crosstalk of CD58(+)DSCs and CD2(+)CD4(+)T cells. Mouse model with sleep disturbance was established to explore the effect of Rev-erbα - GFPT1 - CD58 - CD2 axis on pregnancy. RESULTS: We found that glycometabolism related GFPT1, which regulated by Rev-erbα, increased CD58 expression via glycosylphosphatidylinositol modification not classical N- or O-linked glycosylation modification, leading to the disorder of decidual CD2(+)CD4(+)T cells and consequently, resulting in miscarriage. Anti-CD2 antibody significantly decreased the risk of abortion of SD mice, proving a potential therapeutic target for adverse pregnancy outcomes induced by circadian rhythm disruption. CONCLUSIONS: Rev-erbα - GFPT1 - CD58 - CD2 axis played important role in pregnancy maintenance by regulating the crosstalk between DSCs and decidual CD4(+)T cells. Given that poor sleep is a common problem during pregnancy, our findings may have important implications for understanding the etiology of RPL and developing targeted therapy of RPL. In addition, we should pay attention to the sleep health of pregnant women, especially those with a history of RPL.