title: Cis-acting pathways selectively enforce the non-immunogenicity of shed placental antigen for maternal CD8 T cells.
abstract: Maternal immune tolerance towards the fetus and placenta is thought to be established in part by pathways that attenuate T cell priming to antigens released from the placenta into maternal blood. These pathways remain largely undefined and their existence, at face value, seems incompatible with a mother's need to maintain a functional immune system during pregnancy. A particular conundrum is evident if we consider that maternal antigen presenting cells, activated in order to prime T cells to pathogen-derived antigens, would also have the capacity to prime T cells to co-ingested placental antigens. Here, we address this paradox using a transgenic system in which placental membranes are tagged with a strong surrogate antigen (ovalbumin). We find that although a remarkably large quantity of acellular ovalbumin-containing placental material is released into maternal blood, splenic CD8 T cells in pregnant mice bearing unmanipulated T cell repertoires are not primed to ovalbumin even if the mice are intravenously injected with adjuvants. This failure was largely independent of regulatory T cells, and instead was linked to the intrinsic characteristics of the released material that rendered it selectively non-immunogenic, potentially by sequestering it from CD8α(+) dendritic cells. The release of ovalbumin-containing placental material into maternal blood thus had no discernable impact on CD8 T cell priming to soluble ovalbumin injected intravenously during pregnancy, nor did it induce long-term tolerance to ovalbumin. Together, these results outline a major pathway governing the maternal immune response to the placenta, and suggest how tolerance to placental antigens can be maintained systemically without being detrimental to host defense.
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, New York, United States of America.
authors.forename: Chin-Siean
authors.initials: CS
authors.lastname: Tay
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, New York, United States of America.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tagliani
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, New York, United States of America.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Collins
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, New York, United States of America ; NYU Cancer Institute, NYU School of Medicine, New York, New York, United States of America.
authors.forename: Adrian
authors.initials: A
authors.lastname: Erlebacher
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005333:Fetus / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology*; D010920:Placenta / Q000276:immunology*; D011247:Pregnancy; D054400:Receptors, CCR7 / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D010047:Ovalbumin