Four Core Genotypes Mice Exhibit Quantitative Differences in T and B Cell Subpopulations compared to Wild-type Mice

It has been well established that females have a more active immune system. Females respond better to vaccines, are more resistant to somatic cell cancers, display better pathogen responses, present antigens better, and, conversely, are more prone to autoimmune diseases compared to male counterparts. Though these trends have been observed across normal and pathogenic states, the mechanisms underlying these sex differences have not been fully explained. Some hormonal effects on immune cell populations have been reported, but much less is known about effects contributed by genes on the sex chromosomes, for example those that are more highly expressed in females due to X inactivation escape, or Y-linked genes those unique to males. Here we use the Four Core Genotypes (FCG) mouse model and wildtype XY male mice to disentangle the effects of sex hormones, sex chromosome complement, and their interactions on baseline B and T cell populations in the periphery and T cells in the thymus. We test the effects of a previously described X-Y chromosomal translocation and those of the Sry transgene insertion on chromosome 3. We observe that mice harboring the Sry transgene show significant depletion of peripheral CD8+ T cell subpopulations. In the thymus, the XY XY,but not the XX males, show significant decrease to both CD8+ and CD4+ single positive T cells and an increase to CD4/CD8 double positive T cells. We also show that Y chromosome-bearing mice exhibit depletion in splenic marginal zone B cells. Our data suggests that the gonadal sex is the strongest contributor to this phenotype. Our studies define a critical framework for the use of this model and provide valuable data to assess the use of the FCGs model, especially for diseases involving the immune response.