title: Neonatal innate cytokine responses to BCG controlling T-cell development vary between populations.
abstract: BACKGROUND
  The protective effect of Mycobacterium bovis BCG vaccination against infection and atopy varies between populations.
  
  
  OBJECTIVE
  To identify differences in neonatal responses to BCG between diverse populations and study longitudinal associations with memory T-cell responses.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Telethon Institute for Child Health Research, Center for Child Health Research, University of Western Australia, Perth, Australia. Anitav@ichr.uwa.edu.au
authors.forename: Anita H J
authors.initials: AH
authors.lastname: van den Biggelaar
authors.forename: Susan L
authors.initials: SL
authors.lastname: Prescott
authors.forename: Marjut
authors.initials: M
authors.lastname: Roponen
authors.forename: Marie A
authors.initials: MA
authors.lastname: Nadal-Sims
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Devitt
authors.forename: Suparat
authors.initials: S
authors.lastname: Phuanukoonnon
authors.forename: William
authors.initials: W
authors.lastname: Pomat
authors.forename: Meri K
authors.initials: MK
authors.lastname: Tulic
authors.forename: Deborah
authors.initials: D
authors.lastname: Lehmann
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.forename: Peter C
authors.initials: PC
authors.lastname: Richmond
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Holt
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D001500:BCG Vaccine / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D015999:Multivariate Analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D014373:Tuberculin
chemical_list: D000998:Antiviral Agents; D001500:BCG Vaccine; D016207:Cytokines; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014373:Tuberculin; D007371:Interferon-gamma