title: Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation.
abstract: In malaria-endemic areas, the first exposure to malaria antigens often occurs in utero when the fetal immune system is poised towards the development of tolerance. Children exposed to placental malaria have an increased risk of clinical malaria in the first few years of life compared to unexposed children. Recent work has suggested the potential of pregnancy-associated malaria to induce immune tolerance in children living in malaria-endemic areas. A study was completed to evaluate the effect of malaria exposure during pregnancy on fetal immune tolerance and effector responses.
  
  
  
  Using cord blood samples from a cohort of mother-infant pairs followed from early in pregnancy until delivery, flow cytometry analysis was completed to assess the relationship between pregnancy-associated malaria and fetal cord blood CD4 and dendritic cell phenotypes.
  
  
  
  Cord blood FoxP3+Tregcounts were higher in infants born to mothers with Plasmodium parasitaemia early in pregnancy (12-20 weeks of gestation; p = 0.048), but there was no association between Tregcounts and the presence of parasites in the placenta at the time of delivery (by loop-mediated isothermal amplification (LAMP); p = 0.810). In contrast, higher frequencies of activated CD4 T cells (CD25+FoxP3-CD127+) were observed in the cord blood of neonates with active placental Plasmodium infection at the time of delivery (p = 0.035). This population exhibited evidence of effector memory differentiation, suggesting priming of effector T cells in utero. Lastly, myeloid dendritic cells were higher in the cord blood of infants with histopathologic evidence of placental malaria (p < 0.0001).
  
  
  
  Together, these data indicate that in utero exposure to malaria drives expansion of both regulatory and effector T cells in the fetus, and that the timing of this exposure has a pivotal role in determining the polarization of the fetal immune response.
authors.affiliation: Department of Pediatrics, University of California-San Francisco, 3333 California Street, Suite 315, Box 1234, San Francisco, CA, 94143, USA.
authors.forename: Mary
authors.identifier: 0000-0003-0091-2731
authors.initials: M
authors.lastname: Prahl
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Jagannathan
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Tara I
authors.initials: TI
authors.lastname: McIntyre
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Ann
authors.initials: A
authors.lastname: Auma
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Lila
authors.initials: L
authors.lastname: Farrington
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Samuel
authors.initials: S
authors.lastname: Wamala
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Mayimuna
authors.initials: M
authors.lastname: Nalubega
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Musinguzi
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Kate
authors.initials: K
authors.lastname: Naluwu
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Esther
authors.initials: E
authors.lastname: Sikyoma
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Budker
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Vance
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Odorizzi
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Patience
authors.initials: P
authors.lastname: Nayebare
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: John
authors.initials: J
authors.lastname: Ategeka
authors.affiliation: Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, PO Box 7475, Kampala, Uganda.
authors.forename: Abel
authors.initials: A
authors.lastname: Kakuru
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Diane V
authors.initials: DV
authors.lastname: Havlir
authors.affiliation: School of Medicine, College of Health Sciences, Makerere University of College of Health Sciences, PO Box 7072, Kampala, Uganda.
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Pediatrics, University of California-San Francisco, 3333 California Street, Suite 315, Box 1234, San Francisco, CA, 94143, USA. Margaret.feeney@ucsf.edu.|Department of Medicine, University of California-San Francisco, 3333 California Street, Suite 315, San Francisco, CA, 94143, USA. Margaret.feeney@ucsf.edu.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Feeney
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007231:Infant, Newborn; D008288:Malaria / Q000276:immunology*; D010922:Placenta Diseases / Q000276:immunology*; D010961:Plasmodium / Q000276:immunology*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology*; D055815:Young Adult
keywords: CD4 T cells; Dendritic cells; Fetal immune response; Immune tolerance; Loop-mediated isothermal amplification; Pregnancy-associated malaria