Neonatal innate cytokine responses to BCG controlling T-cell development vary between populations

Abstract

The protective effect of Mycobacterium bovis BCG vaccination against infection and atopy varies between populations. To identify differences in neonatal responses to BCG between diverse populations and study longitudinal associations with memory T-cell responses. Cord blood mononuclear cells were collected from Papua New Guinean (PNG) and Western Australian (WA) newborns. Toll-like receptor (TLR)-2, TLR4, and TLR9 mRNA expression and in vitro BCG-stimulated (+/-IFN-gamma priming) innate cytokine responses were compared. When PNG infants were 3 months old, PBMCs were stimulated in vitro with Mycobacterium-purified protein derivative (PPD) to determine memory T-cell responses. BCG-induced IL-10 and IFN-gamma responses were significantly higher in cord blood mononuclear cells of PNG newborns, and TLR2 and TLR9 expression was significantly higher and TLR4 expression lower compared with WA newborns. High neonatal IL-10 and low IFN-gamma responses to BCG were found to promote the development of PPD-memory T(H)2 responses in infancy, whereas neonatal BCG-TNFalpha responses inhibited the development of PPD-IL 10 responses. When primed with IFN-gamma, BCG-induced TNF-alpha, IL-12p70, and in particular IFN-gamma responses were enhanced to a significantly higher extent in WA than in PNG newborns. In response to IFN-gamma priming and BCG stimulation, natural killer cells of WA newborns produced IFN-gamma, whereas natural killer cells of PNG newborns contributed only indirectly to this response. Neonatal BCG-related innate immune responses control the differentiation of T(H) memory responses and vary between populations. This may explain differences in the effects of BCG vaccination between populations.