On the role of dendritic cells in peripheral T cell tolerance and modulation of autoimmunity.
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 CD8alpha(-)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 FcgammaR 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 FcgammaR-deficient mice where both uptake of Ig-MOG and IL-10 production are compromised. However, reconstitution of these mice with DC populations incorporating the CD8alpha(-)CD4(+) subset restored Ig-MOG-mediated reversal of EAE. Transfer of CD8alpha(+) or even CD8alpha(-)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.
Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA.
Kevin L
KL
Legge
Randal K
RK
Gregg
Roberto
R
Maldonado-Lopez
Lequn
L
Li
Jacque C
JC
Caprio
Muriel
M
Moser
Habib
H
Zaghouani
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D003713:Dendritic Cells / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D006023:Glycoproteins; D008074:Lipoproteins; D008565:Membrane Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10