Abstract
Dendritic cells (DCs) appear in higher numbers within the CNS as a consequence of inflammation associated with autoimmune disorders, such as multiple sclerosis, but the contribution of these cells to the outcome of disease is not yet clear. Here, we show that stimulatory or tolerogenic functional states of intracerebral DCs regulate the systemic activation of neuroantigen-specific T cells, the recruitment of these cells into the CNS and the onset and progression of experimental autoimmune encephalomyelitis (EAE). Intracerebral microinjection of stimulatory DCs exacerbated the onset and clinical course of EAE, accompanied with an early T-cell infiltration and a decreased proportion of regulatory FoxP3-expressing cells in the brain. In contrast, the intracerebral microinjection of DCs modified by tumor necrosis factor alpha induced their tolerogenic functional state and delayed or prevented EAE onset. This triggered the generation of interleukin 10 (IL-10)-producing neuroantigen-specific lymphocytes in the periphery and restricted IL-17 production in the CNS. Our findings suggest that DCs are a rate-limiting factor for neuroinflammation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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Central Nervous System / cytology
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Central Nervous System / immunology*
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Central Nervous System Stimulants
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Dendritic Cells / classification
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Disease Models, Animal
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Encephalomyelitis, Autoimmune, Experimental / chemically induced
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / pathology*
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Female
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Flow Cytometry
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Forkhead Transcription Factors / metabolism
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Freund's Adjuvant / adverse effects
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Glycoproteins / adverse effects
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Immune System Phenomena / drug effects
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Immune System Phenomena / immunology*
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Interferon-alpha / administration & dosage
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Interferon-gamma / metabolism
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Interleukin-7 / metabolism
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Lipopolysaccharides / administration & dosage
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Mice
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Mice, Inbred C57BL
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Mycobacterium tuberculosis
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments / adverse effects
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Picrotoxin / administration & dosage
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T-Lymphocytes / classification
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T-Lymphocytes / immunology
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Time Factors
Substances
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Central Nervous System Stimulants
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Glycoproteins
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Interferon-alpha
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Interleukin-7
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Lipopolysaccharides
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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myelin oligodendrocyte glycoprotein (35-55)
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Picrotoxin
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Interferon-gamma
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Freund's Adjuvant