title: NKG2D blockade inhibits poly(I:C)-triggered fetal loss in wild type but not in IL-10-/- mice.
abstract: Infection and inflammation can disturb immune tolerance at the maternal-fetal interface, resulting in adverse pregnancy outcomes. However, the underlying mechanisms for detrimental immune responses remain ill defined. In this study, we provide evidence for immune programming of fetal loss in response to polyinosinic:polycytidylic acid (polyI:C), a viral mimic and an inducer of inflammatory milieu. IL-10 and uterine NK (uNK) cells expressing the activating receptor NKG2D play a critical role in poly(I:C)-induced fetal demise. In wild type (WT) mice, poly(I:C) treatment induced expansion of NKG2D(+) uNK cells and expression of Rae-1 (an NKG2D ligand) on uterine macrophages and led to fetal resorption. In IL-10(-/-) mice, NKG2D(-) T cells instead became the source of fetal resorption during the same gestation period. Interestingly, both uterine NK and T cells produced TNF-α as the key cytotoxic factor contributing to fetal loss. Treatment of WT mice with poly(I:C) resulted in excessive trophoblast migration into the decidua and increased TUNEL-positive signal. IL-10(-/-) mice supplemented with recombinant IL-10 induced fetal loss through NKG2D(+) uNK cells, similar to the response in WT mice. Blockade of NKG2D in poly(I:C)-treated WT mice led to normal pregnancy outcome. Thus, we demonstrate that pregnancy-disrupting inflammatory events mimicked by poly(I:C) are regulated by IL-10 and depend on the effector function of uterine NKG2D(+) NK cells in WT mice and NKG2D(-) T cells in IL-10 null mice.
authors: Department of Pediatrics, Women and Infants Hospital of Rhode Island-Warren Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA.
authors: Jessica E
authors: JE
authors: Thaxton
authors: Tania
authors: T
authors: Nevers
authors: Eliana O
authors: EO
authors: Lippe
authors: Sandra M
authors: SM
authors: Blois
authors: Shigeru
authors: S
authors: Saito
authors: Surendra
authors: S
authors: Sharma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D020964:Embryo Loss / Q000139:chemically induced* / Q000235:genetics* / Q000517:prevention & control; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D011070:Poly I-C / Q000009:adverse effects*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation; D014599:Uterus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D011070:Poly I-C