title: Activation of Salmonella Typhi-specific regulatory T cells in typhoid disease in a wild-type S. Typhi challenge model.
abstract: Salmonella Typhi (S. Typhi), the causative agent of typhoid fever, causes significant morbidity and mortality worldwide. Currently available vaccines are moderately efficacious, and identification of immunological responses associated with protection or disease will facilitate the development of improved vaccines. We investigated S. Typhi-specific modulation of activation and homing potential of circulating regulatory T cells (Treg) by flow and mass cytometry using specimens obtained from a human challenge study. Peripheral blood mononuclear cells were obtained from volunteers pre- and at multiple time-points post-challenge with wild-type S. Typhi. We identified differing patterns of S. Typhi-specific modulation of the homing potential of circulating Treg between volunteers diagnosed with typhoid (TD) and those who were not (No TD). TD volunteers demonstrated up-regulation of the gut homing molecule integrin α4ß7 pre-challenge, followed by a significant down-regulation post-challenge consistent with Treg homing to the gut. Additionally, S. Typhi-specific Treg from TD volunteers exhibited up-regulation of activation molecules post-challenge (e.g., HLA-DR, LFA-1). We further demonstrate that depletion of Treg results in increased S. Typhi-specific cytokine production by CD8+ TEM in vitro. These results suggest that the tissue distribution of activated Treg, their characteristics and activation status may play a pivotal role in typhoid fever, possibly through suppression of S. Typhi-specific effector T cell responses. These studies provide important novel insights into the regulation of immune responses that are likely to be critical in protection against typhoid and other enteric infectious diseases.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Monica A
authors.initials: MA
authors.lastname: McArthur
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fresnay
authors.affiliation: Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Magder
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Waddington
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.affiliation: Microbial Pathogenesis Group, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Nuffield Department of Medicine, University of Oxford, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D013058:Mass Spectrometry; D008875:Middle Aged; D008954:Models, Biological; D012485:Salmonella typhi / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014435:Typhoid Fever / Q000276:immunology* / Q000382:microbiology; D055815:Young Adult