Antagonizing Peroxisome Proliferator-Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice

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 (PPAR alpha) 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 PPAR alpha functions within CD4(+) and CD8(+) T lymphocytes and NKT cells to negatively regulate IFN-gamma responses in male mice and identified Ifng as the gene target of PPAR alpha repression. Treatment of male CD4+ T cells with the PPAR alpha agonist fenofibrate induced the recruitment of PPAR alpha 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-gamma production. In contrast, treatment of male T cells with IS001, a novel antagonist of PPAR alpha, increased Ifng gene expression and histone acetylation across the Ifng locus. Finally, we investigated the effects of IS001 on IFN-gamma responses in mice during infection with the Th1-associated pathogen Listeria monocytogenes and observed that IS001 enhanced IFN-gamma 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-gamma responses are more robust in females and introduce a small-molecule IS001 that can be used to enhance Th1 immunity in males.