Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific.
Pharmacologic inhibition of indoleamine 2,3 dioxygenase (IDO) activity during murine pregnancy results in rejection of allogeneic fetuses by the maternal immune system. Here, we show that IDO expression is restricted to perinuclear regions of primary trophoblast giant cells (TGCs) of fetal origin at mid-gestation (E10.5). After placentation (E14), no IDO expression was detected at the maternal-fetal interface. Matings involving IDO-deficient females revealed that paternally inherited IDO alleles were inactive in primary TGCs, presumably due to paternal genome-specific gene inactivation. Allogeneic matings in which both parents were genetically IDO-deficient produced litters of normal sizes at normal rates compared to IDO-sufficient parental mice, implying that compensatory or redundant immunosuppressive mechanisms protected allogeneic fetuses during gestation in IDO-deficient mice. Consistent with this notion, treatment with IDO inhibitor did not affect allogeneic pregnancy rates when both parents were IDO-deficient, confirming that IDO was the relevant pharmacologic target of the IDO inhibitor in matings involving IDO-sufficient mice. Hence, IDO is a key immunosuppressive mechanism in normal murine pregnancies, and it is regulated entirely through maternally inherited fetal genes.
Baban
Babak
B
Department of Medicine, Institute of Molecular Medicine and Genetics, Medical College of Georgia 1120, 15th Street, Augusta, GA 30912-2600, USA.
Chandler
Phillip
P
McCool
Doris
D
Marshall
Brendan
B
Munn
David H
DH
Mellor
Andrew L
AL
D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000276:immunology; D016678:Genome; D015726:Giant Cells / Q000201:enzymology / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008297:Male; D008431:Maternal-Fetal Exchange / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D013045:Species Specificity; D014327:Trophoblasts / Q000201:enzymology* / Q000276:immunology; D014366:Tryptophan Oxygenase / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014366:Tryptophan Oxygenase