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 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 CD4(+) and 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.
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
Monan Angela
MA
Zhang
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
Jeeyoon Jennifer
JJ
Ahn
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
Fei Linda
FL
Zhao
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
Thirumahal
T
Selvanantham
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
Thierry
T
Mallevaey
Inception Sciences, San Diego, CA 92121;
Nick
N
Stock
Inception Sciences, San Diego, CA 92121;
Lucia
L
Correa
Inception Sciences, San Diego, CA 92121;
Ryan
R
Clark
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada;
David
D
Spaner
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2M1, Canada; and Women's College Research Institute, Toronto, Ontario M5G 2M1, Canada sdunn@uhnresearch.ca.
Shannon E
SE
Dunn
D000107:Acetylation; D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D011345:Fenofibrate / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011726:Pyridinium Compounds / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012737:Sex Factors; D018417:Th1 Cells / Q000276:immunology*
D000178:Acrylamides; D006657:Histones; C543903:IS 001; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D047493:PPAR alpha; D011726:Pyridinium Compounds; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D011345:Fenofibrate