Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy

TY - JOUR

T1 - Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy

AU - Klotz, Luisa

AU - Dani, Indra

AU - Edenhofer, Frank

AU - Nolden, Lars

AU - Evert, Bernd

AU - Paul, Bianca

AU - Kolanus, Waldemar

AU - Klockgether, Thomas

AU - Knolle, Percy

AU - Diehl, Linda

PY - 2007/2/15

Y1 - 2007/2/15

N2 - 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.

AB - 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.

KW - Adoptive Transfer

KW - Animals

KW - Antigen Presentation

KW - Cell Differentiation

KW - Clonal Anergy

KW - Dendritic Cells

KW - Female

KW - Interleukin-12

KW - Mice

KW - Mice, Inbred BALB C

KW - PPAR gamma

KW - Th1 Cells

KW - Th2 Cells

M3 - SCORING: Journal article

C2 - 17277116

VL - 178

SP - 2122

EP - 2131

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 4

ER -