PPAR gamma ablation in CD4+ T-cells augments T-cell responses in vivo and facilitates disease induction in experimental autoimmune encephalomyelitis

The peroxisome proliferator-activated receptor gamma (PPARg) belongs to a group of ligand-activated transcription factors involved in the regulation of metabolism and inflammation. PPARg is expressed in cells of the peripheral immune compartment like lymphocytes and dendritic cells, but also within the CNS, mainly in microglial cells and in neurons. Interestingly, oral administration of PPARg agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. However, it is still unclear which cell type is primarily involved in PPARg-mediated suppression of (auto)-immunity. Therefore, we generated mice with a T cell specific knock-out of PPARg employing a Cre-recombinase mediated ablation of PPARg which is limited to CD4-expressing T cells. In these mice (CD4-PPARg-KO) and their Cre negative wild-type littermates, we investigated both disease course and T cell responses during actively induced MOG-EAE.

CD4-PPARg-KO mice exhibited both an earlier disease onset and signficantly increased disease severity during the induction phase of EAE when compared to their wild-type littermates. Accordingly, both peripheral T cell responses and T cell infiltration of the CNS were strongly enhanced in CD4-PPARg-KO mice. CNS infiltration in CD4-PPARg-KO mice was characterized by a profound increase in the frequency of IFN-g and IL-17 producing antigen-specific T cells. On the molecular level, PPARg ablation in T cells resulted in a profound increase in NF-kB baseline activity and an enhanced induction of NF-kB DNA-binding activity upon T cell receptor stimulation, thus indicating that PPARg operates as a brake of NF-kB-mediated T cell activity.

These data demonstrate that ablation of PPARg enhances CD4+ T cell autoreactivity resulting in pronounced T cell responses and increased disease induction in a model of CD4+ T cell mediated CNS autoimmunity. Selective activation of PPARg in T cells therefore represents a promising future target for control of multiple sclerosis.