Kristina Shkirkova, BSc

Beckmann L, Obst S, Labusek N, Abberger H, Köster C, Klein-Hitpass L, Schumann S, Kleinschnitz C, Hermann DM, Felderhoff-Müser U, et al. Regulatory T Cells Contribute to Sexual Dimorphism in Neonatal Hypoxic-Ischemic Brain Injury. Stroke. 2022.

Regulatory T cells (Tregs) are specialized T cells that have an ability to suppress immune response. Recent evidence suggests a sexual dimorphism in the role Tregs play after brain injury.

In the study recently published in Stroke by Beckmann et al., experimental administration of hypoxia-ischemia to neonatal mice by ligation of the right common carotid artery, as a model of neonatal encephalopathy, resulted in increased cerebral Tregs infiltration into the brain. Flow cytometry revealed that females experienced significantly higher frequency and total amount of Treg infiltration than males 24 hours after the induced hypoxia-ischemia in the brain but not in the peripheral tissue. To further investigate the functional contribution of Tegs in both sexes, a special agent, DTX, was used to deplete the number of Tregs in mice. As a result of Treg depletion, a more significant injury was observed in female cortex and hippocampus, while in males, the injury was decreased in these areas. Depletion of Tregs also resulted in functional deficits only in females in early forelimb coordination test as well as long-term exploratory activity. In the hippocampus, Treg depletion increased microglial response, endothelial activation, and leukocyte accumulation in female compared to non-depleted females. Females were also observed to have increased basil lamina disruption following Treg depletion, while for males, Treg depletion provided vascular protection. These differences between sexes were not explained by levels of female hormone estradiol, as there was not a difference observed in serum estradiol levels between males and females. Independent of sex hormones, female Tregs were immunosuppressive on effector T cell compared with male, with Myc Targets, mTORC1 signaling and oxidative phosphorylation pathways showing prominence in gene set enrichment analysis.

This analysis provides evidence of sexual dimorphism in Treg function and its effect on glial and endothelial activation, vascular damage and peripheral immune cell infiltration in hypoxia-ischemia injury. This implies an increased anti-inflammatory role female Tregs play in the brain during the acute disease phase compared with a more pro-inflammatory profile observed in males. Further analysis is needed to study in more detail molecular pathways determining these sex specific differences and their potential therapeutic targets.