Tolerance of activated pathogenic CD4+ T cells by transcriptional targeting of dendritic cells.
We have recently shown that targeted expression of myelin oligodendrocyte glycoprotein (MOG) to dendritic cells with self-inactivating-lentivirus vectors induces antigen-specific tolerance in naive antigen-specific CD4+ T cells and protects mice from experimental autoimmune encephalomyelitis (EAE). In the present study, we demonstrate that this approach also induces tolerance of activated antigen-specific CD4+ T cells and completely protects mice from passive EAE induction. Tolerance induction did not correlate with the depletion of the preactivated antigen-specific CD4+ T cells. However, upon isolation and in vitro re-stimulation at day 6 after adoptive transfer the MOG-specific CD4+ T cells from the non-tolerized mice produced large amounts of inflammatory cytokines, whereas those from tolerized mice did not. This unresponsiveness correlated with the upregulation of regulatory molecules associated with anergy and regulatory T cells (Tregs). The in vivo depletion of Tregs resulted in EAE susceptibility of the tolerized animals, suggesting that these cells have indeed a role in tolerance induction/maintenance.
Institute of Virology, University of Zürich, Zürich, Switzerland.
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de Andrade Pereira
Institute of Virology, University of Zürich, Zürich, Switzerland.
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Ackermann
Institute of Virology, University of Zürich, Zürich, Switzerland.
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Chaudhary
Institute of Virology, University of Zürich, Zürich, Switzerland.
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Vogel
Institute of Virology, University of Zürich, Zürich, Switzerland.
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Vogt
Institute of Virology, University of Zürich, Zürich, Switzerland.
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Dresch
Institute of Virology, University of Zürich, Zürich, Switzerland.
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Fraefel
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D015854:Up-Regulation
D016207:Cytokines; C585905:MOG(38-49) peptide, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments