title: The effect of declining exposure on T cell-mediated immunity to Plasmodium falciparum - an epidemiological "natural experiment".
abstract: BACKGROUND
  Naturally acquired immunity to malaria may be lost with lack of exposure. Recent heterogeneous reductions in transmission in parts of Africa mean that large populations of previously protected people may lose their immunity while remaining at risk of infection.
  
  
  METHODS
  Using two ethnically similar long-term cohorts of children with historically similar levels of exposure to Plasmodium falciparum who now experience very different levels of exposure, we assessed the effect of decreased parasite exposure on antimalarial immunity. Peripheral blood mononuclear cells (PBMCs) from children in each cohort were stimulated with P. falciparum and their P. falciparum-specific proliferative and cytokine responses were compared.
  
  
  RESULTS
  We demonstrate that, while P. falciparum-specific CD4+T cells are maintained in the absence of exposure, the proliferative capacity of these cells is altered considerably. P. falciparum-specific CD4+T cells isolated from children previously exposed, but now living in an area of minimal exposure ("historically exposed") proliferate significantly more upon stimulation than cells isolated from children continually exposed to the parasite. Similarly, PBMCs from historically exposed children expressed higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines after stimulation with P. falciparum. Notably, we found a significant positive association between duration since last febrile episode and P. falciparum-specific CD4+T cell proliferation, with more recent febrile episodes associated with lower proliferation.
  
  
  CONCLUSIONS
  Considered in the context of existing knowledge, these data suggest a model explaining how immunity is lost in absence of continuing exposure to P. falciparum.
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.|The Francis Crick Institute, London, NW7 1AA, UK.
authors.forename: Yaw
authors.initials: Y
authors.lastname: Bediako
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.
authors.forename: Joyce Mwongeli
authors.initials: JM
authors.lastname: Ngoi
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.
authors.forename: George
authors.initials: G
authors.lastname: Nyangweso
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.
authors.forename: Juliana
authors.initials: J
authors.lastname: Wambua
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.
authors.forename: Michael
authors.initials: M
authors.lastname: Opiyo
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.
authors.forename: Eunice Wambui
authors.initials: EW
authors.lastname: Nduati
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.|Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya.|Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research (Coast), Box 230, 80108, Kilifi, Kenya. fndungu@kemri-wellcome.org.
authors.forename: Francis Maina
authors.initials: FM
authors.lastname: Ndungu
keywords: Immunity; Malaria; T cells