title: Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy.
abstract: Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+T cells displaying a GARP+CD127loFOXP3+phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil-T cell interactions in the regulation of vascularization at the maternal-fetal interface.
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, United Kingdom; s.nadkarni@qmul.ac.uk.
authors.forename: Suchita
authors.initials: S
authors.lastname: Nadkarni
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Smith
authors.affiliation: Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1TN, United Kingdom.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Sferruzzi-Perri
authors.affiliation: Institute for Women's Health, University College London Hospitals, London NW1 2BU, United Kingdom.
authors.forename: Agata
authors.initials: A
authors.lastname: Ledwozyw
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Madhav
authors.initials: M
authors.lastname: Kishore
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Haas
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mauro
authors.affiliation: Institute for Women's Health, University College London Hospitals, London NW1 2BU, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Williams
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, 05508-000 São Paulo, Brazil.
authors.forename: Sandra H P
authors.initials: SH
authors.lastname: Farsky
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000328:Adult; D000818:Animals; D003656:Decidua / Q000502:physiology; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000502:physiology; D055785:Gene Knockdown Techniques; D064368:Healthy Volunteers; D006801:Humans; D007107:Immune System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D009504:Neutrophils / Q000166:cytology*; D010641:Phenotype; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D055815:Young Adult
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1
keywords: T cells; neutrophils; placenta; pregnancy; regulatory