title: Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans.
abstract: BACKGROUND
  Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection.
  
  
  METHODS
  Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a).
  
  
  RESULTS
  Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM.
  
  
  CONCLUSIONS
  These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore Street, Suite 480, Baltimore, MD, 21201, USA. sfresnay@medicine.umaryland.edu.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fresnay
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore Street, Suite 480, Baltimore, MD, 21201, USA. mmcarthu@medicine.umaryland.edu.
authors.forename: Monica A
authors.initials: MA
authors.lastname: McArthur
authors.affiliation: Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA. LMAGDER@epi.umaryland.edu.
authors.forename: Laurence
authors.initials: L
authors.lastname: Magder
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK. thomas.darton@jesus.ox.ac.uk.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK. claire.jones@paediatrics.ox.ac.uk.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK. Claire.Waddington@telethonkids.org.au.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Waddington
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK. christoph.blohmke@paediatrics.ox.ac.uk.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK. brian.angus@ndm.ox.ac.uk.
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore Street, Suite 480, Baltimore, MD, 21201, USA. Mlevine@medicine.umaryland.edu.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK. andrew.pollard@paediatrics.ox.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore Street, Suite 480, Baltimore, MD, 21201, USA. msztein@medicine.umaryland.edu.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D012485:Salmonella typhi / Q000276:immunology*; D013045:Species Specificity; D016896:Treatment Outcome; D014435:Typhoid Fever / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D055815:Young Adult