Altered composition of peripheral immune subsets in Four Core Genotype mice 2260628

Abstract Introduction Sex-biased immune differences affect autoimmune disease prevalence, susceptibility to infections and anti-tumor responses. The genetic, hormonal and environmental factors that contribute to these differences are difficult to disentangle. Four Core Genotype (FCG) mice harbor an inactivated Sry gene on the Y chromosome (hereafter Sry* and Y*) and an autosomal Sry transgene (Sry-tg) on chromosome 3, allowing the generation of gonadal females with XX and XY* genotypes, and Sry-tg-bearing XX and XY* gonadal males, thereby separating genetic and hormonal/gonadal influences in sex-biased phenotypes. The FCG model has been widely used to investigate sex-linked genetic vs hormonal factors in developmental, behavioral and immune phenotypes. Recently, a 9-gene translocation, including the Tlr7 and Tlr8 genes, was identified on the Y* chromosome. In addition, several genes with potential immune significance are known to flank the Sry-tg insertion site. Methods To evaluate the effect of these genetic alterations on baseline immunity in FCG mice we carried out flow cytometry on peripheral blood, thymus, spleen and superficial lymph nodes of mice of each of the 4 FCG genotypes and wild-type C57BL/6 male controls. Results Mice bearing the Sry-tg (FCG XX and XY* males) showed a 3- to 5-fold reduction in peripheral CD8+ T cell fractions (p < 0.01 compared to WT males), but not in the thymus, arguing against a CD8 T cell development defect. B cell analysis identified a significant ∼2-fold decrease in splenic marginal zone B cell fractions in FCG XY* males and females, which bear the 9-gene Y* translocation (p < 0.01 compared to WT males and XX females). Conclusion These results indicate that baseline immune subset composition is significantly altered in FCG mice, differentially affecting T and B cell populations depending on the genotype. Transcriptional and immunological effects associated with these differences, and their potential impact on immune responses to tumors and pathogens will be discussed. Funding Source Camden Cancer Research Center Seed Grant Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)