title: Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy.
abstract: 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 gamma (PPARgamma) is a negative regulator of DC maturation and function. Sustained PPARgamma 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 PPARgamma-deficient DCs, generated by Cre-mediated ablation of the PPARgamma gene, agonist-mediated suppression of maturation-induced functional changes were abrogated. Moreover, absence of PPARgamma increased DC immunogenicity, suggesting a constitutive regulatory function of PPARgamma in DCs. Adoptive transfer of PPARgamma-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 PPARgamma is an efficient regulator of DC immunogenicity that may be exploited to deliberately target CD4(+) T cell-mediated immune responses.
authors.affiliation: Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany. luisa.klotz@ukb.uni-bonn.de
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.forename: Indra
authors.initials: I
authors.lastname: Dani
authors.forename: Frank
authors.initials: F
authors.lastname: Edenhofer
authors.forename: Lars
authors.initials: L
authors.lastname: Nolden
authors.forename: Bernd
authors.initials: B
authors.lastname: Evert
authors.forename: Bianca
authors.initials: B
authors.lastname: Paul
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kolanus
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D017635:Clonal Anergy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D047495:PPAR gamma / Q000172:deficiency / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D047495:PPAR gamma; D018664:Interleukin-12