title: De novo-induced self-antigen-specific Foxp3+ regulatory T cells impair the accumulation of inflammatory dendritic cells in draining lymph nodes.
abstract: Foxp3(+) regulatory T cell (Treg)-based immunotherapy holds promise for autoimmune diseases. However, this effort has been hampered by major caveats, including the low frequency of autoantigen-specific Foxp3(+) Tregs and lack of understanding of their molecular and cellular targets, in an unmanipulated wild-type (WT) immune repertoire. In this study, we demonstrate that infusion of myelin in WT mice results in the de novo induction of myelin-specific Foxp3(+) Tregs in WT mice and amelioration of experimental autoimmune encephalomyelitis. Myelin-specific Foxp3(+) Tregs exerted their effect both by diminishing Ag-bearing inflammatory dendritic cell (iDC) recruitment to lymph nodes and by impairing their function. Transcriptome analysis of ex vivo-isolated Treg-exposed iDCs showed significant enrichment of transcripts involved in functional properties of iDCs, including chemotaxis-related genes. To this end, CCR7 expression by iDCs was significantly downregulated in tolerant mice and this was tightly regulated by the presence of IL-10. Collectively, our data demonstrate a novel model for deciphering the Ag-specific Foxp3(+) Treg-mediated mechanisms of tolerance and delineate iDCs as a Foxp3(+) Treg cellular target in unmanipulated mice.
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300 Heraklion, Greece; Laboratory of Autoimmunity and Inflammation, University of Crete Medical School, 71300 Heraklion, Greece; Division of Clinical, Experimental Surgery, & Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;
authors.forename: Themis
authors.initials: T
authors.lastname: Alissafi
authors.affiliation: Division of Clinical, Experimental Surgery, & Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Hatzioannou
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300 Heraklion, Greece;
authors.forename: Marianna
authors.initials: M
authors.lastname: Ioannou
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany; and.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Grün
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Grützkau
authors.affiliation: Division of Clinical, Experimental Surgery, & Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece; pverginis@bioacademy.gr.
authors.forename: Panayotis
authors.initials: P
authors.lastname: Verginis
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D002633:Chemotaxis / Q000276:immunology; D016000:Cluster Analysis; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D007108:Immune Tolerance; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D054400:Receptors, CCR7; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10