title: Unstable Foxp3+ regulatory T cells and altered dendritic cells are associated with lipopolysaccharide-induced fetal loss in pregnant interleukin 10-deficient mice.
abstract: Maternal interleukin (IL) 10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here, we show that Il10 null mutant (Il10(-/-)) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4(+) and CD8(+) T cells compared with wild-type controls. Among these CD4(+) cells, Foxp3(+) T regulatory (Treg) cells were substantially enriched, with 11-fold higher numbers at Day 9.5 postcoitum. Lymph node hypertrophy in Il10(-/-) mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor, and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10(-/-) mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2, and Ifng. In vitro, Il10(-/-) Treg cells showed reduced steady-state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4(+)Foxp3(-) T cells. We conclude that despite a substantially expanded Treg cell pool, the diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10(-/-) mice. These findings suggest that IL10 has a pivotal role in facilitating robust immune protection of the fetus from inflammatory challenge and that IL10 deficiency could contribute to human gestational disorders in which altered T cell responses are implicated.
authors.affiliation: The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jelmer R
authors.initials: JR
authors.lastname: Prins
authors.affiliation: The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Bihong
authors.initials: B
authors.lastname: Zhang
authors.affiliation: The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Schjenken
authors.affiliation: The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Leigh R
authors.initials: LR
authors.lastname: Guerin
authors.affiliation: The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Barry
authors.affiliation: The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia sarah.robertson@adelaide.edu.au.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Robertson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D020964:Embryo Loss / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008198:Lymph Nodes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011225:Pre-Eclampsia / Q000235:genetics; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D020381:Interleukin-17; D008070:Lipopolysaccharides; D016753:Interleukin-10
keywords: cytokines; dendritic cells; fetal loss; immunology; inflammation; interleukin 10; preeclampsia; pregnancy; regulatory T cells