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Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy
* Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany;
Department of Neurology, University of Bonn, Bonn, Germany;
Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation, Bonn, Germany; and
Life and Medical Sciences Institute, Program Unit Molecular Immune and Cell Biology, University of Bonn, Bonn, Germany
There is increasing evidence that dendritic cell (DC) immunogenicity is not only positively regulated by ligands of pattern recognition receptors, but also negatively by signals that prevent DC activation and full functional maturation. Depending on their activation status, DCs can induce either immunity or tolerance. In this study, we provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor 
(PPAR) is a negative regulator of DC maturation and function. Sustained PPAR activation in murine DCs reduced maturation-induced expression of costimulatory molecules and IL-12, and profoundly inhibited their capacity to prime naive CD4+ T cells in vitro. Using PPAR-deficient DCs, generated by Cre-mediated ablation of the PPAR gene, agonist-mediated suppression of maturation-induced functional changes were abrogated. Moreover, absence of PPAR increased DC immunogenicity, suggesting a constitutive regulatory function of PPAR in DCs. Adoptive transfer of PPAR-activated Ag-presenting DCs induced CD4+ T cell anergy, characterized by impaired differentiation resulting in absent Th1 and Th2 cytokine production and failure of secondary clonal expansion upon restimulation. Collectively, our data support the notion that PPAR is an efficient regulator of DC immunogenicity that may be exploited to deliberately target CD4+ T cell-mediated immune responses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Luisa Klotz, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. E-mail address: luisa.klotz{at}ukb.uni-bonn.de
2 Abbreviations used in this paper: DC, dendritic cell; PPAR, peroxisome proliferator-activated receptor ; PIO, pioglitazone; k.o., knockout; BMDC, bone marrow DC; 7-AAD, 7-aminoactinomycin D; wt, wild type.
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