title: HLA-G promotes myeloid-derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4.
abstract: Establishing and maintaining maternal-fetal tolerance is essential for a successful pregnancy; failure of immunological adaptation to pregnancy leads to severe complications such as abortion or preterm delivery. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that suppress T-cell responses, expand during pregnancy and thus may play a role in tolerance induction. Human leucocyte antigen G (HLA-G) is a major histocompatibility complex (MHC) I molecule with immune-modulatory properties, which is expressed during pregnancy. Here, we investigated the impact of HLA-G on MDSCs accumulation and activation in pregnant women. We demonstrate that granulocytic MDSCs (GR-MDSCs) express receptors for HLA-G, namely immunoglobulin-like transcript (ILT) 2 and 4, and that ILT4-expression by GR-MDSCs is regulated during pregnancy. Stimulation with soluble HLA-G (sHLA-G) increased suppressive activity of GR-MDSCs, induced MDSCs from peripheral blood mononuclear cells (PBMCs) and led to phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and induction of indoleamine-2,3-dioxygenase (IDO) in myeloid cells. Effects of sHLA-G on MDSC accumulation were mediated through ILT4. These results suggest an interaction between MDSCs and HLA-G in humans as a potential mechanism for maintaining maternal-fetal tolerance. Modulating MDSC function during pregnancy via HLA-G might provide new opportunities for a therapeutic manipulation of immunological pregnancy complications.
authors.affiliation: Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Köstlin
authors.affiliation: Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Ostermeir
authors.affiliation: Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Spring
authors.affiliation: Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schwarz
authors.affiliation: Am Lustnauer Tor, Tuebingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marmé
authors.affiliation: Department of Obstetrics and Gynecology, Tuebingen, Germany.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Walter
authors.affiliation: Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Poets
authors.affiliation: Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gille
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D059951:HLA-G Antigens / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D033261:Maternal-Fetal Relations; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D011247:Pregnancy; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D059951:HLA-G Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor
keywords: HLA-G; MDSC; Reproductive Immunology; T cells; Tolerance