Abstract
Females have more robust immune responses than males, well-illustrated by the degree of inflammation elicited during delayed-type hypersensitivity (DTH) responses. Here, we have investigated underlying sex differences that may contribute to differential footpad DTH responses using wildtype and four core genotypes (FCG) mice and popliteal lymphnode cellularity and gene expression. DTH responses in XX and XY FCG females showed no role for almost all genes expressed on sex chromosomes. After then filtering-out genes differentially expressed between XX and XY females, only one gene was sexually differentially expressed in wildtype mice, glycosylation-dependent cell adhesion molecule 1 (Glycam1), expressed 7-fold higher in females. Glycam1 facilitates leukocyte entry through high endothelial venules. Consistent with greater Glycam1 expression, female nodes contained twice as many cells. While females had more memory T cells in their nodes, males had a higher percentage of T regulatory cells. This sexual dimorphism in wildtype animals manifested pre-pubertally, was enhanced post-pubertally, and was eliminated by castration. The formation of male gonads is determined by the expression of Sry. Sry overexpression, which does not affect testosterone levels, produced an exaggerated male phenotype. We conclude that Sry expression through formation of the male gonad indirectly negatively impacts the potential for local inflammation.
Highlights
Females are considered to have stronger cell-mediated immune responses compared to males
We showed that female mice exhibit larger T cell-mediated delayed-type hypersensitivity (DTH) responses when compared to male mice[6]
A footpad DTH response involves a major influx of cells, many of which come via lymphnodes in the region
Summary
Females are considered to have stronger cell-mediated immune responses compared to males. Others have shown that female mice survive longer than males when infected with Mycobacterium marinum[5] These and other studies provide documentation of sexual dimorphism in T cell-mediated immune responses, relatively little is known about causal factors for these acute responses or differences between the sexes that exist at steady state. A model system that allows a determination of the separate roles of gonadal hormones and almost all X and Y genes is the Four Core Genotypes (FCG) mouse. In this model, the Sry gene, which is responsible for development as a male, has been deleted from the Y chromosome (Y-) and reintroduced as a transgene onto an autosome. For later discussion of results, Sry is overexpressed in the male FCG mice, there is no difference in circulating testosterone levels between adult FCG and wildtype males[10]
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