title: Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions.
abstract: Organ transplantation represents a unique therapeutic option for irreparable organ dysfunction and rejection of transplants results from a breakdown in operational tolerance. Although endothelial cells (ECs) are the first target in graft rejection following kidney transplantation, their capacity to alloactivate and generate particular T lymphocyte subsets that could intervene in this process remains unknown. By using an experimental model of microvascular endothelium, we demonstrate that, under inflammatory conditions, human ECs induced proliferation of memory CD4(+)CD45RA(-) T cells and selectively amplified proinflammatory Th17 and suppressive CD45RA(-)HLA-DR(+)FoxP3(bright) regulatory CD4(+) T lymphocytes (Tregs). Although HLA-DR expression on resting microvascular ECs was sufficient to induce proliferation of memory CD4(+) T cells, Treg amplification was dependent on the interaction with CD54, highly expressed only under inflammatory conditions. Moreover, expansion of Th17 cells was dependent on IL-6 and STAT-3, and inhibition of either specifically impaired Th17, without altering Treg expansion. Collectively these data reveal that the HLA-DR(+) ECs regulate the local inflammatory allogeneic response, promoting either an IL-6/STAT-3-dependent Th17 response or a contact-CD54-dependent regulatory response according to the cytokine environment. Finally, these data open therapeutic perspectives in human organ transplantation based on targeting the IL-6/STAT-3 pathway and/or promoting CD54 dependent Treg proliferation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Santé 940, Hôpital Saint Louis, 75010 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Taflin
authors.forename: Benoit
authors.initials: B
authors.lastname: Favier
authors.forename: Jeremy
authors.initials: J
authors.lastname: Baudhuin
authors.forename: Alain
authors.initials: A
authors.lastname: Savenay
authors.forename: Patrice
authors.initials: P
authors.lastname: Hemon
authors.forename: Armand
authors.initials: A
authors.lastname: Bensussan
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.forename: Denis
authors.initials: D
authors.lastname: Glotz
authors.forename: Nuala
authors.initials: N
authors.lastname: Mooney
mesh_terms: D049109:Cell Proliferation; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology
chemical_list: D006684:HLA-DR Antigens; D015850:Interleukin-6; D009841:Oligonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018799:Intercellular Adhesion Molecule-1