A Model to Explain How the Bacille Calmette Guérin (BCG) Vaccine Drives Interleukin-12 Production in Neonates

• Published in: PloS one 2016-08, Vol.11 (8), p.e0162148-e0162148
• Main Authors: Kativhu, Chido Loveness, Libraty, Daniel H
• Format: Article
• Language: English
• Subjects: Antigens; Bacilli; Bacillus Calmette-Guerin vaccine; BCG; BCG Vaccine - pharmacology; Biology and Life Sciences; Birth; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Cells, Cultured; Cloning; Consent; Cytokines; Dendritic cells; Deoxyribonucleic acid; DNA; Fetal Blood - cytology; Flow Cytometry; Humans; Immune response; Immune system; Immunology; Infant, Newborn; Infectious diseases; Interferon; Interleukin 12; Interleukin-12 - genetics; Interleukin-12 - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Ligands; Lymphocytes T; Medicine and Health Sciences; Monocytes; Mortality; mRNA; Mycobacterium; Mycobacterium bovis; Mycobacterium tuberculosis; Natural killer cells; Neonates; Newborn babies; Proteins; RNA, Messenger - genetics; Signaling; T cell receptors; TLR2 protein; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Toxins; Tuberculosis; Umbilical cord; Vaccination; Vaccines; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0162148

The Bacille Calmette Guérin (BCG) vaccine is the only routine vaccination at birth that effectively induces neonatal T-helper 1 (Th1)-polarized immune responses. The primary cytokine that drives CD4+ T-cell Th1 differentiation is interleukin (IL)-12 p70, a heterodimeric cytokine composed of the IL-12 p35 and IL-12 p40 subunits. We therefore examined the mechanisms involved in BCG vaccine stimulation of IL-12 p35 and p40 production from human umbilical cord (neonatal) cells. We found that BCG bacilli did not upregulate IL-12 p35 mRNA production, but upregulated IL-12 p40 mRNA production in a Toll-like receptor (TLR)2-dependent manner, in human neonatal monocyte-derived dendritic cells (mdDCs). The combination of TLR2 signaling, Type I interferon (IFN), and Type II IFN induced maximal levels of IL-12 p35 and p40 mRNA production in human neonatal mdDCs. The cell-free supernatants of reconstituted BCG vaccine vials contained extracellular mycobacterial (BCG) DNA which could induce IFN-α (Type I IFN) production in human neonatal plasmacytoid dendritic cells (pDCs). BCG bacilli also stimulated human neonatal CD16lo natural killer (NK) cells to produce IFN-γ (Type II IFN) in a TLR2-dependent manner. We have therefore proposed a model where BCG vaccine could stimulate the combination of neonatal conventional DCs (cDCs), pDCs, and CD16lo NK cells to produce optimal neonatal IL-12 p35 and p40 (IL-12 p70) production and subsequent CD4+ T-cell Th1 polarization. An adjuvant that emulates the mechanism by which the BCG vaccine stimulates neonatal IL-12 p35 and p40 production could improve vaccine strategies at birth for protection against intracellular pathogens and toxins.