Abstract
Using four core genotypes (FCG) mice, we have previously shown a larger number of CD4+ and CD8+ T cells in the spleens of female mice, a sex difference that develops by postnatal day 7 and is retained through adulthood. This difference in splenic T cell number is a consequence of reduced thymic egress and reduced splenic seeding in male mice, caused in part by the male-specific perinatal surge of testosterone, and in part by Sry, which is overexpressed in this model. Here, we used the background strain for FCG mice (C57BL/6J) to ask whether sex influenced actual immunity in the postnatal period. Pups were immunized on postpartum days 1 or 3 with Mycobacterium tuberculosis (Mtb), challenged on day 7 with Mtb purified protein derivative (PPD), and sacrificed on day 8. Subsequent ex vivo challenges of splenocytes showed PPD-stimulated CD8+ responses (increased CD8+, increased CD8+CD44hi, decreased CD8+CD44hiCD127-/lo) but no differences between males and females. However, when CD8+ T cells were analyzed for IFN-γ and IL-2 production, although there was no sex difference in mono-functional IFN-γ+ (100%) or IL-2+ (67%), only females (0% of males and 42% of females) produced bi-functional (IFN-γ+IL-2+) cells. Ex vivo PPD-stimulated responses of other relevant cells from the spleen showed no sex differences in dendritic cells (CD11c+CD86+IL-6+) but females had more (3-fold) IL-6-producing macrophages (F4/80+CD86+IL-6+) and reduced T regulatory cells (CD4+CD25+Foxp3+). We conclude that some sex differences in immunity are evident at one week of age in Mtb immunized mouse pups, with females exhibiting qualitatively superior Mtb-specific immune responses.
Keywords
Improvement in neonatal immunity, Sex differences in neonatal immunity, Tuberculosis, Bi-functional CD8+ T cells, Perinatal testosterone surge, Male bias in TB susceptibility