Cis-acting pathways selectively enforce the non-immunogenicity of shed placental antigen for maternal CD8 T cells

• Published in: PloS one 2013-12, Vol.8 (12), p.e84064-e84064
• Main Authors: Tay, Chin-Siean, Tagliani, Elisa, Collins, Mary K, Erlebacher, Adrian
• Format: Article
• Language: English
• Subjects: Adjuvants; Adjuvants, Immunologic - administration & dosage; Albumin; Animals; Antigen presentation; Antigen Presentation - immunology; Antigen-presenting cells; Antigens; Biology; Blood; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cloning; Dendritic cells; Dendritic Cells - immunology; Female; Fetus - immunology; Fetuses; Flow Cytometry; Genetic engineering; Hostages; Immune response; Immune system; Immune Tolerance - immunology; Immunogenicity; Immunological tolerance; Immunoregulation; Infections; Lymphocytes; Lymphocytes T; Medicine; Membranes; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Ovalbumin - immunology; Pathology; Placenta; Placenta - immunology; Pregnancy; Pregnant women; Priming; Receptors, CCR7 - physiology; Sequestering; Spleen; T cell receptors; T cells; T-Lymphocytes, Regulatory - immunology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084064

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.