Abstract
Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4+ and CD8+ T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet+CD4+ T cells, CD8+ T cells, B cells, and CD56loCD16+ NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.
This article is featured in In This Issue, p.4181
Footnotes
This work was supported by the March of Dimes Prematurity Research Center at Stanford and the Bill and Melinda Gates Foundation (OPP 1017093, OPP1113682); additional funding was provided by the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University. G.K.F. was supported by a Stanford Bio-X graduate research fellowship (Stanford, CA) and National Institutes of Health Grant T32GM007276. B.L.G. was supported by National Institutes of Health Grant 1K23GM111657-02. This work was also supported in part by the Child Health Research Institute (to R.J.W., G.M.S., and D.K.S.); the Mary L. Johnson Research Fund (to R.J.W. and D.K.S.); the Christopher Hess Research Fund (to R.J.W. and D.K.S.); National Institutes of Health Grants 5R01AI10012104 (to D.B.L.), U19AI057229 (to G.P.N.), and 1U19AI100627 (to G.P.N.); and Food and Drug Administration Grant HHSF223201210194C (to G.P.N.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- C
- Cesarean
- cDC
- classical dendritic cell
- cMC
- classical monocyte
- CSM
- cell-staining medium
- FDR
- false discovery rate
- MAPKAPK2
- MAPK-activated protein kinase 2
- MDSC
- myeloid-derived suppressor cell
- SAM
- significance analysis of microarrays
- Treg
- regulatory T cell.
- Received July 11, 2016.
- Accepted September 20, 2016.
- Copyright © 2016 by The American Association of Immunologists, Inc.