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: Themis Alissafi, Aikaterini Hatzioannou, Marianna Ioannou, Tim Sparwasser, Joachim R Grün, Andreas Grützkau, Panayotis Verginis
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 12 Pg. 5812-24 (Jun 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25948818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Autoantigens
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Myelin-Oligodendrocyte Glycoprotein
• Peptide Fragments
• Receptors, CCR7
• myelin oligodendrocyte glycoprotein (35-55)
• Interleukin-10

Topics

• Animals
• Autoantigens (immunology)
• Autoimmunity
• Chemotaxis (immunology)
• Cluster Analysis
• Dendritic Cells (immunology)
• Disease Models, Animal
• Disease Progression
• Encephalomyelitis, Autoimmune, Experimental (genetics, immunology, metabolism)
• Female
• Forkhead Transcription Factors (metabolism)
• Gene Expression Profiling
• Immune Tolerance
• Inflammation (genetics, immunology, metabolism)
• Interleukin-10 (metabolism)
• Lymph Nodes (immunology)
• Lymphocyte Depletion
• Mice
• Mice, Knockout
• Myelin-Oligodendrocyte Glycoprotein (administration & dosage, immunology)
• Peptide Fragments (administration & dosage, immunology)
• Receptors, CCR7 (genetics, metabolism)
• Signal Transduction
• T-Cell Antigen Receptor Specificity (immunology)
• T-Lymphocytes, Regulatory (immunology, metabolism)