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Establishment of fetomaternal tolerance via glycan-mediated B cell suppression

ABSTRACT: The immune system must be able to distinguish self from non-self. During pregnancy, the mother’s immune system does not recognize the placenta as foreign because proteins expressed by tropbholasts, the placental cells that interface with the maternal immune system, do not activate maternal T cells. These activation defects have been previously attributed to suppression by regulatory T cells, while mechanisms of maternal B cell tolerance to trophoblast antigens have not been identified. In this study, we provide evidence that glycan-mediated B cell suppression plays a key role in establishing fetomaternal tolerance in mice. We find that trophoblast antigen-specific B cells are profoundly suppressed via CD22/LYN inhibitory signaling, in turn implicating the antigens’ sialic acids as key suppressive determinants. We also find that B cells mediate the antigen’s MHCII-restricted presentation to CD4 T cells, leading to T cell suppression. The specific goal of the mass spectrometry undertaking deposited here was to identify sialylated “true” placental-derived proteins present in the human and mouse serum proteome during pregnancy. Overall, our findings reveal protein glycosylation as a fundamental feature of placental “self-recognition” and may have relevance to pregnancy complications and tumor immune evasion. Furthermore, we anticipate these findings will enhance synthetic efforts to harness glycans to control antigen-specific immune responses in the treatment of autoimmune diseases.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Blood Serum

SUBMITTER: Sami Tuomivaara

LAB HEAD: Susan J Fisher

PROVIDER: PXD029966 | Pride | 2022-01-12

REPOSITORIES: Pride

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Establishment of fetomaternal tolerance through glycan-mediated B cell suppression.

Rizzuto G G Brooks J F JF Tuomivaara S T ST McIntyre T I TI Ma S S Rideaux D D Zikherman J J Fisher S J SJ Erlebacher A A

Nature 20220302 7901

Discrimination of self from non-self is fundamental to a wide range of immunological processes1. During pregnancy, the mother does not recognize the placenta as immunologically foreign because antigens expressed by trophoblasts, the placental cells that interface with the maternal immune system, do not activate maternal T cells2. Currently, these activation defects are thought to reflect suppression by regulatory T cells3. By contrast, mechanisms of B cell tolera ...[more]

PMID: 35236989

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Project description:The role of extracellular vesicles (EVs), specifically exosomes, in intercellular communication likely plays a key role in placental orchestration of pregnancy and maternal immune sensing of the fetus. While murine models are powerful tools to study pregnancy and maternal-fetal immune interactions, in contrast to human placental exosomes, the content of murine placental and pregnancy exosomes remains largely understudied. Using a recently developed in vitro culture technique, murine trophoblast stem cells derived from B6 mice were differentiated into syncytial-like cells. EVs from the conditioned media, as well as from pregnant and non-pregnant sera, were enriched for exosomes. The RNA composition of these murine trophoblast-derived and pregnancy-associated exosome-enriched-EVs (ExoE-EVs) was determined using RNA-sequencing analysis and expression levels confirmed by qRT-PCR. Differentially abundant miRNAs were detected in syncytial differentiated ExoE-EVs, particularly from the X chromosome cluster (mmu-miR-322-3p, mmu-miR-322-5p, mmu-miR-503-5p, mmu-miR-542-3p, and mmu-miR-450a-5p). These were confirmed to be increased in pregnant mouse sera ExoE-EVs by qRT-PCR analysis. Interestingly, fifteen miRNAs were only present within the pregnancy-derived ExoE-EVs compared to non-pregnant controls. Mmu-miR-292-3p and mmu-miR-183-5p were noted to be some of the most abundant miRNAs in syncytial ExoE-EVs and were also present at higher levels in pregnant versus non-pregnant sera ExoE-EVs. The bioinformatics tool, MultiMir, was employed to query publicly available databases of predicted miRNA-target interactions. This analysis reveals that the X-chromosome miRNAs are predicted to target ubiquitin-mediated proteolysis and intracellular signaling pathways. Knowing the cargo of placental and pregnancy-specific ExoE-EVs as well as the predicted biological targets informs studies using murine models to examine not only maternal-fetal immune interactions but also the physiologic consequences of placental-maternal communication.

Project description:Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, precise phenotyping of the preterm birth is hampered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. The studyâ??s aim was to comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor using precisely phenotyped samples. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified the four groups of patients: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). The largest differences in gene expression among the four groups occurred in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5â?? and 3â??UTR regions. The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection. 183 total RNA samples from 8 tissue types collected from 35 women grouped into six categories of pregnancy outcome. One microarray replicate per sample. Other Contributors: Radek Bukowski, Sam Parry and the NICHD Genomic and Proteomic Network for Preterm Birth Research

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Establishment of fetomaternal tolerance via glycan-mediated B cell suppression

Publications

Establishment of fetomaternal tolerance through glycan-mediated B cell suppression.

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