title: Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans.
abstract: BACKGROUND
  Immunity to malaria develops naturally in endemic regions, but the protective immune mechanisms are poorly understood. Many vaccination strategies aim to induce T cells against diverse pre-erythrocytic antigens, but correlates of protection in the field have been limited. The objective of this study was to investigate cell-mediated immune correlates of protection in natural malaria. Memory T cells reactive against thrombospondin-related adhesive protein (TRAP) and circumsporozoite (CS) protein, major vaccine candidate antigens, were measured, as were frequencies of CD4(+) CD25(high) T cells, which may suppress immunity, and CD56(+) NK cells and gammadelta T cells, which may be effectors or may modulate immunity.
  
  
  RESULTS
  112 healthy volunteers living in rural Kenya were entered in the study. Memory T cells reactive against TRAP and CS were measured using a cultured IFNgamma ELISPOT approach, whilst CD4(+) CD25(high) T cells, CD56(+) NK cells, and gammadelta T cells were measured by flow cytometry. We found that T cell responses against TRAP were established early in life (<5 years) in contrast to CS, and cultured ELISPOT memory T cell responses did not correlate with ex-vivo IFNgamma ELISPOT effector responses. Data was examined for associations with risk of clinical malaria for a period of 300 days. Multivariate logistic analysis incorporating age and CS response showed that cultured memory T cell responses against TRAP were associated with a significantly reduced incidence of malaria (p = 0.028). This was not seen for CS responses. Higher numbers of CD4(+) CD25(high) T cells, potentially regulatory T cells, were associated with a significantly increased risk of clinical malaria (p = 0.039).
  
  
  CONCLUSIONS
  These data demonstrate a role for central memory T cells in natural malarial immunity and support current vaccination strategies aimed at inducing durable protective T cell responses against the TRAP antigen. They also suggest that CD4(+) CD25(high) T cells may negatively affect naturally acquired malarial immunity.
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine, Oxford University, Churchill Hospital, Oxford, United Kingdom. stephen.todryk@unn.ac.uk
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Todryk
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.forename: Tabitha
authors.initials: T
authors.lastname: Mwangi
authors.forename: Magdalena
authors.initials: M
authors.lastname: Plebanski
authors.forename: Britta
authors.initials: B
authors.lastname: Urban
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Katie L
authors.initials: KL
authors.lastname: Flanagan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044383:Black People; D015704:CD4 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D042541:Intracellular Space / Q000378:metabolism; D007630:Kenya / Q000453:epidemiology; D008288:Malaria / Q000453:epidemiology / Q000517:prevention & control*; D008875:Middle Aged; D010641:Phenotype; D015800:Protozoan Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000469:parasitology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D015800:Protozoan Proteins; C069428:thrombospondin-related adhesive protein, protozoan; D007371:Interferon-gamma