It is reported that female CD4+ T cells are biased towards T helper (Th) 1 cytokine production, whereas male CD4+ T cells are biased towards Th2. It has been suggested that the female bias in Th1 immunity is the reason why females not only generate enhanced anti-viral and anti-tumour responses, but also are more likely to develop certain autoimmune diseases than males. Our group previously reported that the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) has a sex-specific role in negatively regulating Th1 immunity in mice. The objective of the thesis is to further explore the roles of PPARα in the regulation of sex differences in Th immunity.
We first investigated sex differences in Th cytokine production in SJL mice and human primary CD4+ T cells. We observed that female CD4+ T cells of both species produced higher levels of interferon (IFN)-γ and lower levels of IL-17 than male counterparts. Furthermore, we showed that this sex bias in Th immunity was controlled by androgens. The effects of androgens in suppressing Th1 immunity were shown to be mediated through PPARα. Moreover, we showed that PPARα activity negatively correlated with IFN-γ production by CD4+ T cells. Subsequent studies in mice identified IFN-γ as the gene repressed by PPARα. We showed that this repression was mediated through the recruitment of PPARα and the nuclear receptor co-repressor 1(NCOR)-containing co-repressor complex to certain conserved non-coding sequences (CNS) at the Ifng locus in male T cells. Conversely, repressing PPARα activity with the antagonist NXT-1120 lead to global derepression at the Ifng locus and increased IFN-γ production. This control of IFN-γ production by PPARα in male T cells also extended to natural killer (NK) T cells and CD8+ T cells.
On the other hand, we found that the sex difference in Th17 immunity was regulated by PPARγ. Androgens decreased PPARγ mRNAs in murine and human CD4+ T cells. Furthermore, knocking down PPARγ expression using siRNAs was associated with higher IL-17 production by female CD4+ T cells. Taken together, these findings have furthered the understanding of sex differences in Th immunity.Ph.D
