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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.