Sex‐specific differences in T‐cell immune dysregulation and aberrant response to inflammatory stimuli in offspring exposed to maternal chronic inflammation

Abstract

Problems: Maternal chronic inflammation (MI) can adversely affect offspring's immune development resulting in dysregulation of splenic T cells. Interleukin 1 beta contributes to mediating inflammation in the placenta to induce fetal toxicity and cause long-term postnatal sequelae. In this study, we investigated how MI affects the T-cell immune development from the fetal to the neonatal period and how offspring responded to postnatal IL-1β challenge when exposed to an adverse intrauterine environment. We also extend these studies to examine the sex-specific differences. Methods of Study: Time-pregnant CD1 dams were administrated with four consecutive injections of mouse recombinant Interleukin-1β (rIL-1β) or phosphate-buffered saline (PBS) from embryonic day (E)14 to E17. Pups were treated with rIL-1β or PBS at postnatal day (PND)11 (pre-weaning) or PND24 (post-weaning). Pups' splenic immune cells were isolated and then characterized using flow cytometry. Results: At PND12, no differences were observed either in Ctrl or MI offspring. At PND25, we observed elevated amount of CD8 + T cells, descending CD4 + /CD8 + and Treg/Teff ratio in MI offspring. Pre-weaning rIL-1β administration did not affect T-cell subpopulation in Ctrl pups while post-weaning rIL-1β administration increased T cells and CD8 + T cells and decreased CD4 + /CD8 + and Treg/Teff ratio in Ctrl offspring. Furthermore, pre-weaning rIL-1β administration decreased the frequency of T cells and Treg/Teff ratio in MI pups while post-weaning rIL-1β administration increased Tregs and Treg/Teff in MI pups. Regarding sex-specific changes, we observed that at PND12, MI females exhibited higher CD4 + /CD8 + and Treg/Teff ratio than Ctrl females. At PND25, we observed elevated amount of CD8 + T cells, descending CD4 + /CD8 + and Treg/Teff ratio in MI Females, while MI males did not show any changes in T-cell population. Pre-weaning rIL-1β administration decreased T-cell frequency in both MI males and females and decreased Treg/Teff ratio only in MI females. Post-weaning rIL-1β administration increased Tregs and Treg/Teff ratio, and decreased CD4 + /CD8 + ratio in MI females.

Depletion of Ly6G-Expressing Neutrophilic Cells Leads to Altered Peripheral T-Cell Homeostasis and Thymic Development in Neonatal Mice

“…Interestingly, increased CD8 + T-cell numbers were found in the offspring of mice with maternal immune activation (MIA) [32]. The latter is associated with impaired neurological development [33].…”