Glutamine metabolism shapes the phenotypic adaptation of uterine dendritic cells in response to early allogeneic pregnancy.

The impact of metabolic reprogramming on immune cell functions is increasingly recognized. However, it remains largely unexplored in terms of immune cell adaptation during reproduction. Dendritic cells (DC) are crucial for establishing and maintaining pregnancy by orchestrating maternal immune adaptation essential for embryo implantation and decidualization. Here, we characterized the phenotypic and metabolic characteristics of DCs during early pregnancy in an allogeneic mouse model and in response to the specific deletion of hormonal receptors on DCs. The frequency of uterine CD11c+ DCs on gestational day 7.5 remained equal to that of nonpregnant mice. However, we observed a functional shift from conventional DC 1 (cDC1) to cDC2 in pregnant mice. In parallel, a metabolic switch in uterine DCs was identified by upregulation of genes representing fatty acid synthesis (fatty acid synthase and acetyl-CoA carboxylase), fatty acid oxidation (carnitine palmitoyltransferase Ia), and glutamine-related metabolic pathways (Got2). The cell-specific deletion of the glucocorticoid receptor in DCs reduced their major histocompatibility complex II expression, accompanied by a reduction in Got2 expression. Glutamine deprivation in vitro dramatically reduced the absolute number of cultured bone marrow cells and the frequency of cDC1s while simultaneously increasing the frequency of cDC2s. Collectively, these findings establish glutamine metabolism as a key driver of DC adaptation during early pregnancy, revealing novel metabolic-immunological cross talk at the maternal-fetal interface.NEW & NOTEWORTHY The present study provides novel insights into the spatiotemporal features of dendritic cells concerning phenotypic and metabolic adaptation in the uterus, the uterus-draining lymph nodes, and peripheral blood mononuclear cells during early pregnancy. It further underscores the fundamental role of glutamine metabolism in regulating uterine dendritic cells to facilitate fetal tolerance, embryo implantation, and promote decidualization.