Main content area

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

Zhang, Monan Angela, Rego, Dorothy, Moshkova, Marina, Kebir, Hania, Chruscinski, Andrzej, Nguyen, HoangKim, Akkermann, Rainer, Stanczyk, Frank Z., Prat, Alexandre, Steinman, Lawrence, Dunn, Shannon E.
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.24 pp. 9505-9510
T-lymphocytes, androgens, autoimmune diseases, females, humans, interleukin-17, males, men, mice, sexual dimorphism, small interfering RNA, transfection, women
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.