title: Prolonged PD1 Expression on Neonatal Vδ2 Lymphocytes Dampens Proinflammatory Responses: Role of Epigenetic Regulation.
abstract: A successful pregnancy depends on the maintenance of tolerance at the fetal-maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections. Human Vδ2 T cells mount innate-like responses to a broad range of microorganisms and are poised for Th1 responses before birth. In infants they likely play a key role in protection against pathogens by exerting early Th1 effector functions, improving function of other innate cells, and promoting Th1 polarization of adaptive responses. However, their propensity to release Th1 mediators may require careful regulation during fetal life to avoid exaggerated proinflammatory responses. We investigated molecules with the potential to act as a rheostat for fetal Vδ2 cells. Programmed death 1 (PD1) is a negative regulator of T cell responses and a determinant of tolerance, particularly at the fetal-maternal interface. Neonatal Vδ2 cells upregulate PD1 shortly after activation and, unlike their adult counterparts, express this molecule for at least 28 d. Engagement of PD1 by one of its ligands, PDL1, effectively dampens TCR-mediated responses (TNF-α production and degranulation) by neonatal Vδ2 cells and may thus help maintain their activity within safe limits. PD1 expression by neonatal Vδ2 cells is inversely associated with promoter DNA methylation. Prolonged PD1 expression may be part of a functional program to control Vδ2 cell inflammatory responses during fetal life.
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD 21201;
authors.forename: Haoting
authors.initials: H
authors.lastname: Hsu
authors.affiliation: Division of Malaria Research at the Institute for Global Health, School of Medicine, University of Maryland, Baltimore, MD 21201;
authors.forename: Sarah
authors.initials: S
authors.lastname: Boudova
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre 3, Malawi; and.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Mvula
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre 3, Malawi; and.
authors.forename: Titus H
authors.identifier: 0000-0003-3029-9579
authors.initials: TH
authors.lastname: Divala
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre 3, Malawi; and.
authors.forename: Randy G
authors.identifier: 0000-0003-2505-0904
authors.initials: RG
authors.lastname: Mungwira
authors.affiliation: Obstetrics, Gynecology and Reproductive Health, University of Maryland, Baltimore, MD 21201.
authors.forename: Christopher
authors.identifier: 0000-0001-9918-5508
authors.initials: C
authors.lastname: Harman
authors.affiliation: Division of Malaria Research at the Institute for Global Health, School of Medicine, University of Maryland, Baltimore, MD 21201;
authors.forename: Miriam K
authors.initials: MK
authors.lastname: Laufer
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD 21201;
authors.forename: C David
authors.initials: CD
authors.lastname: Pauza
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD 21201; ccairo@ihv.umaryland.edu.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Cairo
mesh_terms: D000328:Adult; D060890:B7-H1 Antigen / Q000276:immunology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance; D007231:Infant, Newborn; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation; D011247:Pregnancy; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha