Chorioamnionitis alters the developing immune system and increases inflammatory double negative T cells in young adolescent rats

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Background: Preterm human neonates with CP show sustained peripheral immune activation at school age. Previously, in a clinically relevant rat model of CP, we showed that CHORIO results in a sustained peripheral immune system hyperreactivity using in vitro and in vivo studies with peripheral blood mononuclear cells (PBMC) at term equivalent age and young adolescence. In this study, we set out to study T cell immune responses in CHORIO model in this brain/peripheral immune response interface.  

Objective: To determine whether CHORIO during a critical prenatal immune system developmental window results in sustained adaptive immune system changes at young adolescent age in a clinically relevant rat model of CP. 

Design/Methods: Pregnant Sprague-Dawley rats were stratified to Sham or CHORIO groups and underwent laparotomy on embryonic day 18 (E18). CHORIO was induced by transient occlusion of the uterine arteries followed by intra-amniotic injection of lipopolysaccharide (LPS, 4 μg/sac). Shams received laparotomy with equivalent duration of anesthesia. PBMC's were collected 4-weeks after CHORIO (postnatal day (P) 21). Multicolor flow cytometry was performed on a spectral flow cytometer to determine peripheral blood T-cell subsets. Data was analyzed by De novo software and represented as mean±SEM. Statistical comparisons were made using a Welch's t-test (n=6 CHORIO, n=8 Sham) p<0.05 considered significant. 

Results: We measured adaptive immune responses in peripheral blood T cell subsets in sham and CHORIO pups at P21. We detected a significant increase in the percentage of gated CD3+CD4-CD8- T cells (double negative T cells) in CHORIO (13.56±0.8722) pups compared with Sham (10.33±0.09348) at P21 (p=0.0275). In addition, consistent with human CHORIO literature, there were no significant alterations in percentages of gated peripheral blood T cell subsets, including CD45+CD3+ lymphocytes, CD3+CD4T helper (Th) cells, CD3+CD4+CD25+FoxP3T regulatory (Treg) cells, CD3+CD8+ T cells and CD3-CD4immature T cells. 

Conclusion(s): Increased double negative T cells in peripheral blood of CHORIO pups at P21 correlates with our previous in-vitro culture studies showing sustained peripheral innate immune hyperreactivity in CHORIO pups at P21. Increased peripheral double negative T cells have been shown to be associated with aggravated neuroinflammation in the literature. Thus, our results suggest that pro-inflammatory double negative T cells in CHORIO may contribute to PBI that results in CP in CHORIO. Further characterization of the molecular mechanisms contributing to brain/peripheral immune response interface may result in targeted therapies to alleviate PBI in CHORIO. 

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