Sex hormones and gender influence the expression and function of regulatory T cells differentially in SLE patients

Abstract

Abstract Regulatory T cells have been implicated in the regulation and maintenance of immune homeostasis. Whether gender and sex hormones differentially influence the expression and function of regulatory T cell phenotype and their influence on Foxp3 expression remain obscure. We provide evidence in this study that in humans the number and percent of regulatory T cells expressing CD4+ and CD8+ are significantly reduced in healthy females compared to healthy males. Both CD4+CD25+hiCD127low and CD8+CD25hi+CD127low subsets in healthy males have a 3–4-fold increase in Foxp3 mRNA expression compared to healthy females. Incubation of CD4+ regulatory T cells with 17b- estradiol at physiological levels either maintains or decreases FoxP3 expression in females with SLE, in contrast to inducing a significant increase in CD4+ Treg in healthy females. Of significance, testosterone significantly increases FoxP3 expression in CD4+CD25hiCD127low cells from females with SLE. Furthermore, plasma concentrations of testosterone positively correlate in those females with the expression of FoxP3 in their CD4+CD25+CD127lowT cells. These data demonstrate that females may be more susceptible than males to SLE and other autoimmune diseases in part because healthy females have fewer regulatory T cells and less FoxP3 expression within those cells. In addition, females with SLE, compared to healthy females, have less ability to generate CD4+Treg in response to physiologic concentrations of 17b-estradiol, whereas an active testosterone metabolite increases the generation of CD4+Tregs. These data clearly suggest that gender and sex hormones influence susceptibility to SLE via their effects on regulatory T cells and Foxp3 expression.