Abstract
Mice lacking IL-6 are resistant to autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), which is driven by CNS-reactive CD4(+) T cells. There are multiple cellular sources of IL-6, but the critical source in EAE has been uncertain. Using cell-specific IL-6 deficiency in models of EAE induced by active immunization, passive transfer, T cell transfer, and dendritic cell transfer, we show that neither the pathogenic T cells nor CNS-resident cells are required to produce IL-6. Instead, the requirement for IL-6 was restricted to the early stages of T cell activation and was entirely controlled by dendritic cell-derived IL-6. This reflected the loss of IL-6R expression by T cells over time. These data explain why blockade of IL-6R only achieves protection against EAE if used at the time of T cell priming. The implications for therapeutic manipulation of IL-6 signaling in human T cell-driven autoimmune conditions are considered.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Autoantigens / immunology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / transplantation
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Crosses, Genetic
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / transplantation
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Histocompatibility Antigens Class II / immunology
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Immunization, Passive
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Interleukin-6 / deficiency
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Interleukin-6 / immunology*
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Interleukin-6 / metabolism
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Lymphocyte Activation
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Lymphokines / analysis
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myelin Basic Protein / immunology
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Myelin-Oligodendrocyte Glycoprotein / immunology
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Peptide Fragments / immunology
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Receptors, Interleukin-6 / biosynthesis
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Receptors, Interleukin-6 / immunology
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Specific Pathogen-Free Organisms
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T-Cell Antigen Receptor Specificity
Substances
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Autoantigens
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H-2A(b) antigen, mouse
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Histocompatibility Antigens Class II
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Interleukin-6
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Lymphokines
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Myelin Basic Protein
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Receptors, Interleukin-6
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interleukin-6, mouse
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myelin basic protein 1-9
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myelin oligodendrocyte glycoprotein (35-55)