Immunoregulatory actions of PPAR γ in CD4+ T cells and dendritic cells

Bassaganya-Riera, J. and R. Hontecillas (2006) Immunoregulatory actions of PPAR g in CD4+ T cells and dendritic cells. AAI Annual Meeting, Boston, MA. (Abstract #1125).

Dysregulated immune responses characterized by overproduction of IFN-γ contribute to the pathogenesis inflammatory bowel disease (IBD), type 1 diabetes and multiple sclerosis. Previously, we demonstrated that activation of peroxisome proliferator-activated receptor (PPAR) γ by conjugated linoleic acid ameliorates IBD in mice. Herein, we investigated whether PPAR γ plays an important role in down-regulating CD4+ T cell and dendritic cell (DC) effector functions. We first measured the effect of the deficiency of PPAR γ in CD4+ T cells on IFN-γ production in vitro. We next examined whether the deficiency of PPAR γ in DC would influence their costimulatory ability by analyzing surface CD40 expression in bone-marrow derived DC from PPAR γ null (PPAR γfl/flMMTV-Cre+) or PPAR γ-expressing (PPAR γfl/flMMTV-Cre-) mice. Finally, we investigated the effect of the loss of PPAR γ in DC on ovalbumin (OVA)-specific CD4+ T cell proliferation and IFN-γ production by co-culturing CD4+ T cells from PPAR γ-expressing and PPAR γnull, OVA-immunized mice with OVA-pulsed DC. We show that the loss of PPAR γ in CD4+ T cells resulted in a 13-fold upregulation of IFN-γ production, which was independent of changes in IL-12 receptor expression. We also found that the loss of PPAR γ by DC resulted in upregulation of CD40 – a key determinant of the decision between tolerance and immunity. From the results of co-culture studies we propose that PPAR γ expressed in DC is more important in down-regulating antigen-specific proliferation and IFN-γ production than PPAR γ expressed by CD4+ T cells. Thus, PPAR γ is a key down-regulator of CD4+ T cell and DC function.