title: Human decidual stromal cells suppress cytokine secretion by allogenic CD4+ T cells via PD-1 ligand interactions.
abstract: BACKGROUND
  Although previous reports suggest an antigen-presenting function for decidual stromal cells (DSCs), the relevance of cell-to-cell communication between DSCs and T cells at the human feto-maternal interface has not been fully elucidated. Therefore, we investigated the presence and function of human DSC-expressed B7-H1 and B7-DC co-stimulatory ligands. B7-H1 and B7-DC on peripheral antigen-presenting cells (APC) typically inhibit T cell activation after binding to their corresponding receptor, programmed death-1 (PD-1).
  
  
  METHODS
  DSCs were isolated from human term decidua. The expression of B7-H1/B7-DC and HLA-DR and their alteration following IFN-gamma and/or TNF-alpha stimulation were assessed. DSCs with or without IFN-gamma pretreatment were co-cultured with allogenic CD4(+) T cells. The effect of PD-1:B7-H1/B7-DC and T cell receptor (TCR):HLA-DR interactions on T cell cytokine production was evaluated by adding blocking antibodies.
  
  
  RESULTS
  DSCs constitutively expressed B7-H1 and B7-DC, as well as small amounts of HLA-DR. Exogenous IFN-gamma and TNF-alpha up-regulated the B7-H1/-DC expression on DSCs, whereas HLA-DR expression was increased only by IFN-gamma. IFN-gamma pretreatment of DSCs stimulated T cell cytokine production through HLA-DR up-regulation. B7-H1 blockade on DSCs strongly enhanced T cell cytokine production (IFN-gamma, TNF-alpha and IL-2), whereas B7-DC blockade had similar but more modest effects. Blockade of both B7-H1 and B7-DC resulted in additive effects.
  
  
  CONCLUSIONS
  Our findings support the categorization of human DSCs as non-professional APCs and suggest that PD-1 ligands on DSCs, together with major histocompatibility complex class II, may play a crucial role in the regulation of decidual CD4(+) T cell cytokine production. This helps to maintain a balanced cytokine milieu at the feto-maternal interface.
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Missouri-Columbia, One Hospital Drive, Columbia, MO 65201, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagamatsu
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Schust
authors.forename: Jun
authors.initials: J
authors.lastname: Sugimoto
authors.forename: Breton F
authors.initials: BF
authors.lastname: Barrier
mesh_terms: D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000502:physiology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism*; D003656:Decidua / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008954:Models, Biological; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D006684:HLA-DR Antigens; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger