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 α (PPARα) in male CD4 T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARα inhibits Th1 responses in male mice. In this study, we found that PPARα functions within CD4and CD8 T lymphocytes and NKT cells to negatively regulate IFN-γ responses in male mice and identified Ifng as the gene target of PPARα repression. Treatment of male CD4+T cells with the PPARα agonist fenofibrate induced the recruitment of PPARα 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-γ production. In contrast, treatment of male T cells with IS001, a novel antagonist of PPARα, increased Ifng gene expression and histone acetylation across the Ifng locus. Finally, we investigated the effects of IS001 on IFN-γ responses in mice during infection with the Th1-associated pathogen Listeria monocytogenes and observed that IS001 enhanced IFN-γ 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-γ responses are more robust in females and introduce a small-molecule IS001 that can be used to enhance Th1 immunity in males.

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Date of publication: 21 October 2015; The Journal of Immunology

Author information: Monan Angela Zhang (1); Jeeyoon Jennifer Ahn (1); Fei Linda Zhao (1); Thirumahal Selvanantham (1); Thierry Mallevaey (1); Nick Stock (2); Lucia Correa (2); Ryan Clark (2); David Spaner (1,3,4); & Shannon E. Dunn (1,5,6)

(1) Department of Immunology, Univeristy of Toronto, Toronto, Ontario M5S 1A8, Canada
(2) Inception Sciences, San Diego, CA 92121
(3) Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada
(4) Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
(5) Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2M1, Canada
(6) Women’s College Research Institute, Toronto, Ontario M5G 2M1, Canada

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