On the Role of Dendritic Cells in Peripheral T Cell Tolerance and Modulation of Autoimmunity

• DOI: 10.1084/jem.20011061
• Publication Date: 2002-07-28T22:32:53Z
• Authors: Kevin L. Legge; Randal K. Gregg; Roberto Maldonado...; Lequn Li; Jacque C. Caprio; Muriel Moser; Habib Zaghouani
• Keywords: T-Lymphocytes; Lipoproteins -- genetics; Antigen delivery; Autoimmunity; Recombinant Fusion Proteins -- genetics; Inbred C57BL; Peptide Fragments -- immunology; Dendritic cells; Dendritic Cells -- immunology; T-Lymphocyte Subsets -- immunology; Interleukin-10 -- biosynthesis; Mice; 0302 clinical medicine; T-Lymphocyte Subsets; Receptors; Encephalomyelitis; Mice, Knockout; Membrane Proteins -- genetics; Membrane Proteins -- immunology; Lipoproteins -- immunology; Sciences bio-médicales et agricoles; Interleukin-10; IgG -- deficiency; Self Tolerance; Experimental -- etiology; Recombinant Fusion Proteins -- immunology; Encephalomyelitis, Autoimmune, Experimental; Knockout; Lipoproteins; Recombinant Fusion Proteins; Molecular Sequence Data; Article; 03 medical and health sciences; Animals; Amino Acid Sequence; Glycoproteins; Fcγ receptors; IgG -- genetics; Peripheral T cell tolerance; Receptors, IgG; Experimental -- immunology; Membrane Proteins; Dendritic Cells; Glycoproteins -- genetics; Peptide Fragments -- genetics; Glycoproteins -- immunology; Peptide Fragments; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; T-Lymphocytes -- immunology; Experimental -- prevention & control; Autoimmune

Recently, it has become clear that dendritic cells (DCs) are essential for the priming of T cell responses. However, their role in the maintenance of peripheral T cell tolerance remains largely undefined. Herein, an antigen-presenting cell (APC) transfer system was devised and applied to experimental allergic encephalomyelitis (EAE), to evaluate the contribution that DCs play in peripheral T cell tolerance. The CD8α−CD4+ subset, a minor population among splenic DCs, was found to mediate both tolerance and bystander suppression against diverse T cell specificities. Aggregated (agg) Ig-myelin oligodendrocyte glycoprotein (MOG), an Ig chimera carrying the MOG 35–55 peptide, binds and cross-links FcγR on APC leading to efficient peptide presentation and interleukin (IL)-10 production. Furthermore, administration of agg Ig-MOG into diseased mice induces relief from clinical EAE involving multiple epitopes. Such recovery could not occur in FcγR-deficient mice where both uptake of Ig-MOG and IL-10 production are compromised. However, reconstitution of these mice with DC populations incorporating the CD8α−CD4+ subset restored Ig-MOG–mediated reversal of EAE. Transfer of CD8α+ or even CD8α−CD4− DCs had no effect on the disease. These findings strongly implicate DCs in peripheral tolerance and emphasize their functional potency, as a small population of DCs was able to support effective suppression of autoimmunity.