PPARs by promoting an allosteric change in the ligand-binding domain of the receptor that supports an increased association with coactivator proteins and a decreased association with corepressor proteins such as nuclear receptor corepressor

Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex disparity is a consequence of higher activity of the androgen-induced gene peroxisome proliferator–activated receptor a (PPARa) in male CD4 T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARa inhibits Th1 responses in male mice. In this study, we found that PPARa functions within CD4 and CD8 T lymphocytes and NKT cells to negatively regulate IFN-g responses in male mice and identified Ifng as the gene target of PPARa repression. Treatment of male CD4 T cells with the PPARa agonist fenofibrate induced the recruitment of PPARa and the nuclear receptor-interacting protein, nuclear receptor corepressor 1, to specific cis-regulatory elements in the Ifng locus. This recruitment associated with reduced histone acetylation at these sites. Knockdown of nuclear receptor corepressor 1 in primary male T cells abolished the effect of fenofibrate in reducing IFN-g production. In contrast, treatment of male T cells with IS001, a novel antagonist of PPARa, increased Ifng gene expression and histone acetylation across the Ifng locus. Finally, we investigated the effects of IS001 on IFN-g responses in mice during infection with the Th1-associated pathogen Listeria monocytogenes and observed that IS001 enhanced IFN-g production by NKT, CD4, and CD8 T cells and improved the survival of male, but not female, mice. Our findings provide a novel mechanism of why IFN-g responses are more robust in females and introduce a small-molecule IS001 that can be used to enhance Th1 immunity in males. The Journal of Immunology, 2015, 195: 000–000.