Up-regulation of BTLA expression in myeloid dendritic cells in neonatal sepsis associated with the treatment outcome and down-regulation of DC function

Abstract

Background: Neonatal sepsis is an acute life-threatening condition in neonates, and a proper innate inflammatory is essential for prevention of the systemic inflammation associated with sepsis. As the most potential antigen-presenting innate immune cells, dentritic cells (DCs) dysfunction has been verified detrimental for sepsis. B and T lymphocyte attenuator (BTLA) is an immune-regulatory receptor shown to be associated with DCs dysfunction. However, the role of BTLA expression in myeloid DCs (mDCs) in neonatal sepsis is unknown. Methods: 61 of neonates with sepsis and 32 of neonates having no suspicion of sepsis as control were enrolled into this study. BTLA and HLA-DR expression in mDCs was measured by flow cytometry. To further study the role of BTLA in regulating mDCs function, BTLA+mDCs and BTLA-mDCs from septic neonates were sorted and utilized to evaluate the phagacytosis capacity, bactericidal ability as well as cytokine secretion of mDCs.Results: A higher percentage of BTLA+mDCs were observed in neonatal septic patients and the percentage was positively correlated to the duration of hospitalization of neonates as well as the severity of sepsis. Moreover, a decrease MFI expression of HLA-DR was found in mDCs in neonatal sepsis, which expression was negatively correlated with the percentage of BTLA+mDCs. When compared to BTLA-mDCs, sorted BTLA+mDCs exhibited lower FITC-dextran uptake capacity but more CFU E.coli number after cells challenged by E.coli. In addition, BTLA+mDCs comparatively secreted lower level of TNF-α and IL-12, but higher IL-10. Conclusions: A higher level of BTLA in mDCs in the observed septic neonates was associated to the severity of neonatal sepsis; therefore, BTLA expression in mDCs could be a useful biomarker help to determine the neonatal sepsis development. Additionally, BTLA negatively regulated the phagocytosis capacity and bactericidal ability of mDCs and lowered their antigen-presenting ability as well as altered cells into an anti-inflammatory phenotype. Thus, targeting BTLA in mDCs may be a new therapeutic strategy for neonatal sepsis.