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The Journal of Neuroscience, January 7, 2009, 29(1):140-152; doi:10.1523/JNEUROSCI.2199-08.2009

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Neurobiology of Disease
Intracerebral Dendritic Cells Critically Modulate Encephalitogenic versus Regulatory Immune Responses in the CNS

Alla L. Zozulya,^1,2 Sonja Ortler,¹ JangEun Lee,² Christian Weidenfeller,¹ Matyas Sandor,² Heinz Wiendl,^1 * and Zsuzsanna Fabry^2 *

¹Department of Neurology, University of Würzburg, 97080 Würzburg, Germany, and ²Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, Wisconsin 53706

Correspondence should be addressed to either of the following: Dr. Zsuzsanna Fabry, Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, 1300 University Avenue, 6130 MSC Madison, WI 53706, Email: zfabry{at}wisc.edu; or Dr. Heinz Wiendl, Department of Neurology, University of Würzburg, Josef-Schneider Strasse 11, 97080 Würzburg, Germany, Email: heinz.wiendl{at}klinik.uni-wuerzburg.de

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 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.

Key words: neuroimmunology; dendritic cells; myelin oligodendrocyte glycoprotein antigen; intracerebral injection; T-cell immune responses; neuroinflammation; autoimmunity

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Received May 15, 2008; revised Oct. 8, 2008; accepted Nov. 6, 2008.

Correspondence should be addressed to either of the following: Dr. Zsuzsanna Fabry, Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, 1300 University Avenue, 6130 MSC Madison, WI 53706, Email: zfabry{at}wisc.edu; or Dr. Heinz Wiendl, Department of Neurology, University of Würzburg, Josef-Schneider Strasse 11, 97080 Würzburg, Germany, Email: heinz.wiendl{at}klinik.uni-wuerzburg.de

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