De novo–induced self-antigen–specific Foxp3+ regulatory T cells impair the accumulation of inflammatory dendritic cells in draining lymph nodes

T Alissafi, A Hatzioannou, M Ioannou… - The Journal of …, 2015 - journals.aai.org
T Alissafi, A Hatzioannou, M Ioannou, T Sparwasser, JR Grün, A Grützkau, P Verginis
The Journal of Immunology, 2015journals.aai.org
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 …
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.
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