Women face a four-fold higher risk of developing an autoimmune disease compared to men. Sex differences in immune-mediated disorders are well-documented, but have remained poorly understood and are not taken into account in current therapies. To improve treatment of sex-biased autoimmune disorders it will be essential to gain a much deeper understanding of fundamental factors controlling sex differences in the human immune system. In the present study we apply two complementary human model systems to determine the separate roles of sex hormones and sex chromosomes in immune regulation. In the firs part, we investigate how the immune system is transformed during female-to-male and male-to-female sex change. A combination of broad-scale technologies are applied to follow dynamics provoked by sex hormone transition in peripheral blood immune cells, autoimmune reactivity, plasma proteins, and gut microbiota. As a complementary model to capture effects mediated by sex chromosomes, we study mosaic individuals harboring immune cells with both female and male karyotypes in peripheral blood. Single cell transcriptomic analysis is used to compare these cell populations, thereby revealing the influence of chromosomal sex in an otherwise fixed genetic and hormonal background. This approach can offer insights into the biology of sex differences of human immune systems, thus providing a foundation for development of new treatment strategies for sex-biased autoimmune disorders.