Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS.
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.
Zozulya
Alla L
AL
Department of Neurology, University of Würzburg, 97080 Würzburg, Germany.
Ortler
Sonja
S
Lee
JangEun
J
Weidenfeller
Christian
C
Sandor
Matyas
M
Wiendl
Heinz
H
Fabry
Zsuzsanna
Z
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology*; D000697:Central Nervous System Stimulants; D003713:Dendritic Cells / Q000145:classification / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005620:Freund's Adjuvant / Q000009:adverse effects; D006023:Glycoproteins / Q000009:adverse effects; D055633:Immune System Phenomena / Q000187:drug effects / Q000276:immunology*; D016898:Interferon-alpha / Q000008:administration & dosage; D007371:Interferon-gamma / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000009:adverse effects; D010852:Picrotoxin / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology; D013997:Time Factors
D000697:Central Nervous System Stimulants; D051858:Forkhead Transcription Factors; D005620:Freund's Adjuvant; D006023:Glycoproteins; D016898:Interferon-alpha; D007371:Interferon-gamma; D015851:Interleukin-7; D008070:Lipopolysaccharides; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010852:Picrotoxin; C498833:Foxp3 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55)