Interleukin-27 opposes BCG internalization, clearance, and Th1 cytokine responses in neonatal dendritic cells
Shelby Bradford1,2, Jessica M. Povroznik1,2, and Cory M. Robinson1,2
1Department of Microbiology, Immunology, and Cell Biology; West Virginia University School of Medicine, Morgantown, West Virginia
2Vaccine Development center; West Virginia University School of Medicine, Morgantown, West Virginia
Interleukin (IL)-27 is an immune-suppressive cytokine expressed at elevated levels in the neonatal period. This is important because some vaccines, such as bacille Calmette Guérin (BCG) for protection against the bacterium Mycobacterium tuberculosis (Mtb), are delivered during this early life period. BCG does not provide consistent long-term protection against pulmonary tuberculosis (TB) and fails to reduce the TB burden in many endemic regions. We hypothesize that IL-27 interferes with the development of optimal immune responses during BCG vaccination. To evaluate this hypothesis, we developed a neonatal model of BCG vaccination. Although IL-27 levels are already elevated, C57BL/6 mice vaccinated as neonates continue to increase IL-27 serum levels compared to non-vaccinated controls or adult-vaccinated mice. A rise in IL-27 is consistent with the inability to clear BCG over 5 weeks in any age group. Given their importance in driving vaccine-induced responses, we further studied neonatal dendritic cells (DCs) in vitro. Similar to systemic levels following vaccination, BCG stimulated an increase in IL-27 expression by neonatal DCs. To evaluate the effect of IL-27 on DC function, we utilized IL-27Ra-deficient (KO) mice that fail to respond to IL-27. In the absence of IL-27 signaling, improved internalization and clearance of BCG was observed compared to WT neonatal DCs. In addition to improved BCG clearance, IL-12 production was increased in neonatal DCs from KO compared to WT mice. These studies suggest that IL-27 antagonizes antigen uptake, clearance, and production of Th1 stimulatory factors during BCG vaccination of neonates.