Cutting Edge: Dual Function of PPARγ in CD11c+ Cells Ensures Immune Tolerance in the Airways

The respiratory tract maintains immune homeostasis despite constant provocation by environmental Ags. Failure to induce tolerogenic responses to allergens incites allergic inflammation. Despite the understanding that APCs have a crucial role in maintaining immune tolerance, the underlying mechanisms are poorly understood. Using mice with a conditional deletion of peroxisome proliferator-activated receptor γ (PPARγ) in CD11c(+) cells, we show that PPARγ performs two critical functions in CD11c(+) cells to induce tolerance, thereby preserving immune homeostasis. First, PPARγ was crucial for the induction of retinaldehyde dehydrogenase (aldh1a2) selectively in CD103(+) dendritic cells, which we recently showed promotes Foxp3 expression in naive CD4(+) T cells. Second, in all CD11c(+) cells, PPARγ was required to suppress expression of the Th17-skewing cytokines IL-6 and IL-23p19. Also, lack of PPARγ in CD11c(+) cells induced p38 MAPK activity, which was recently linked to Th17 development. Thus, PPARγ favors immune tolerance by promoting regulatory T cell generation and blocking Th17 differentiation.