Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way.
Women develop certain autoimmune diseases more often than men. It has been hypothesized that this may relate to the development of more robust T-helper (Th)1 responses in women. To test whether women exhibit a Th1 bias, we isolated naïve cluster of differentiation (CD)4(+) T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti-CD3 and anti-CD28. We observed that CD4(+) T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male CD4(+) T cells. Intriguingly, male CD4(+) T cells instead had a predilection toward IL-17A production. This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss/Jackson Laboratory (SJL) mouse. Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T-cell expression of peroxisome proliferator activated receptor (PPAR)α and PPARγ. Androgens increased PPARα and decreased PPARγ expression by human CD4(+) T cells. PPARα siRNA-mediated knockdown had the effect of increasing IFNγ by male CD4(+) T cells, while transfection of CD4(+) T cells with PPARγ siRNAs increased IL-17A production uniquely by female T cells. Together, our observations indicate that human T cells exhibit a sex difference in the production of IFNγ and IL-17A that may be driven by expressions of PPARα and PPARγ.
Department of Immunology,  University of Toronto, Toronto, ON,  Canada M5S 1A8.
Monan Angela
MA
Zhang
Dorothy
D
Rego
Marina
M
Moshkova
Hania
H
Kebir
Andrzej
A
Chruscinski
Hoangkim
H
Nguyen
Rainer
R
Akkermann
Frank Z
FZ
Stanczyk
Alexandre
A
Prat
Lawrence
L
Steinman
Shannon E
SE
Dunn
D000728:Androgens / Q000502:physiology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D012737:Sex Factors; D013601:T-Lymphocytes / Q000378:metabolism*
D000728:Androgens; C508717:IL17A protein, human; D020381:Interleukin-17; D047493:PPAR alpha; D047495:PPAR gamma; D007371:Interferon-gamma