Abstracts (complete list) - Wissenschaft Online

Luisa Klotz, Indra Dani, Linda Diehl, Ari Waisman, Thomas Klockgether, Percy Knolle
PPARgamma ablation in CD4+ T cells augments T cell
responses resulting in enhanced T cell infiltration of the CNS
and increased disease severity during experimental
autoimmune encephalomyelitis
The peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a
group of ligand-activated transcription factors involved in the regulation of metabolism
and inflammation. PPARgamma 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 PPARgamma
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 PPARgamma-mediated
suppression of (auto)-immunity. Therefore, we generated mice with a T cell specific
knock-out of PPARgamma employing a Cre-recombinase mediated ablation of
PPARgamma which is limited to CD4+ 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 a signficantly increased
disease severity during the induction phase of EAE when compared to wild-type mice.
Accordingly, T cell infiltration of the CNS was significantly increased in CD4-PPARg-ko
mice. Moreover, both priming of naïve CD4-PPARg-ko T cells in vitro as well as
restimulation of CD4-PPARg-ko T cells primed in vivo yielded significantly augmented T
cell responses characterized by an increase in T cell proliferation as well as production
of proinflammatory cytokines.
These data demonstrate that ablation of PPARgamma enhances T cell reactivity both in
vitro and in vivo, resulting in pronounced T cell responses and consecutively increased
disease severity in a model of CD4+ T cell mediated autoimmunity. Selective activation
of PPARgamma in T cells therefore represents a promising future target for control of T
cell mediated autoimmunity.