Abstract
Bacille Calmette Guérin (BCG) is a live-attenuated vaccine for protection against Mycobacterium tuberculosis. Despite high disease protection in infancy and early childhood, it generates poor long-term protection against pulmonary tuberculosis. We hypothesized that the unique immune profile that includes elevated interleukin (IL)-27, contributes to insufficient protection from routine neonatal BCG administration. Using a novel method to obtain neonatal progenitors, we showed that neonatal bone marrow-derived dendritic cells (BMDCs) increase production of IL-27 following BCG stimulation. To study the effect of IL-27 on BMDCs, we utilized mice deficient for IL-27 receptor-α (KO). We observed greater BCG clearance and elevated IL-12 production in the neonatal KO BMDCs compared to WT. BMDCs from KO neonates in turn stimulated more interferon-γ production from CD4(+) T cells isolated from BCG-vaccinated mice than WT counterparts. To further confirm the importance of these findings, C57BL/6 mice were vaccinated as neonates in line with the approach to human vaccination in high TB burden regions. IL-27 levels progressively increased through 5 weeks and were significantly elevated in mice vaccinated with BCG compared to controls. The impact of IL-27 production on clearance of BCG was significant as KO mice cleared BCG from peripheral tissues that persisted in WT mice 5 weeks post-vaccination. These results are the first to highlight the suppressive role of IL-27 on DCs in the neonatal period and the impact on neonatal immune responses to BCG.