Sex Differences In T Cell Immune Responses And Outcome After Stroke In Aged Mice

Introduction: Sex differences are increasingly recognized in stroke. Stroke incidence is higher in men than in women until an advanced age and women have higher mortality and morbidity. Inflammatory responses are key determinants of outcome but have not been well studies in aged animals. Hypothesis: We hypothesize that there are important sex differences in inflammation in aged male and female mice. Results: We quantified T cells and T regulatory cells, as well as functional outcome after stroke in aged mice. Male and female C57BL/6 mice (20-21 months) were subjected to 60 min middle cerebral artery occlusion (n=16) by the filament model, or sham surgery (n=7). Immune responses in brain, blood and spleen were investigated 15 days post-stroke by flow cytometry. Functional outcomes were assessed at day 3, 7 and 14. Mortality was 25% in females and occurred at day 1, while in males 50% mortality was seen between day 3 and 9. Hemorrhagic transformation was seen in 53% of the males that died (5/8) and in none of the females (0/4). Flow cytometry analysis at day 15 showed significantly higher levels of CD8 + T cells in the blood after stroke in males compared to females (73±5% of CD3 + T cells vs 52±3%, P<0.001). CD8 + T cells were found in brains from males and females after stroke but levels were not different from sham (Male Stroke: 64±7%, Female Stroke: 58±5%). Independent of the type of surgery (stroke or sham), we observed higher levels of splenic CD8 + T cells in males (P<0.01). T regulatory cells were significantly increased in the brain after stroke in males compared to sham (P<0.01), but not in females. Open-field testing showed a decrease in center visits after stroke in both sexes at 3 days, however males spent more time immobile (P<0.01) indicating decreased locomotor activity and/or anxiety. This difference equalized at 7 and 14 days post-stroke. Conclusion: Higher mortality and hemorrhagic transformation rates were seen in aged males than in females after stroke. This may be associated with the elevated levels of CD8 + T cells in blood and possible unfavorable effects on blood brain barrier permeability.