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

Abstract

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. autoimmunity | cytokines | experimental autoimmune encephalomyelitis | gender | nuclear receptor

The PPARα pathway in Vγ9Vδ2 T cell anergy

“…By contrast, in immune cells PPAR primarily inhibits inflammatory pathways by repressing c-jun and NF-κB [11,12]. PPAR also inhibits IFN responses of human  T cells [13]. Whether PPAR also regulates human  T cell functions remains unclear.…”

Antagonizing Peroxisome Proliferator–Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice

“…One intriguing feature of Th1 immune responses is that they are more robust in females than in males (5)(6)(7)(8). This sex difference is thought to underlie why women generate enhanced antiviral (9) and antitumor (10) immune responses, but also have a higher propensity to develop certain autoimmune diseases (8).…”

“…This sex difference is thought to underlie why women generate enhanced antiviral (9) and antitumor (10) immune responses, but also have a higher propensity to develop certain autoimmune diseases (8). Past studies have suggested that sex differences in Th1 responses arise because of suppressive effects of androgens at key nodes in the Th1 differentiation pathway including IL-12 production (11) and signaling (12,13) and IFN-g production downstream of Ag stimulation (6,7). Until recently, the molecular players involved in this androgen-dependent regulation were not known.…”

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

“…Female immune responses are tilted to Th1 with the dominance of IFN-γ, whereas male responses are pushed to Th17, dominated by IL-17 and IL-23. Dunn showed that this was true across species from mice to humans (97,98). Because PPAR-α is targeted by widely used drugs such as gemfibrozil, this dimorphism provides clues that can be translated to therapy with widely used approved drugs for other indications.…”

“…Shannon Dunn tackled this problem while a postdoc and has continued her brilliant work in a faculty position at the University of Toronto. We published a series of reports in the Journal of Experimental Medicine and Nature Medicine (96)(97)(98) describing the role of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-δ in regulating the sexual dimorphism. PPAR-α is overexpressed on male T cells.…”