title: Expansion of Foxp3(+) T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge.
abstract: Candida albicans remains the fungus most frequently associated with nosocomial bloodstream infection. In disseminated candidiasis, the role of Foxp3(+) regulatory T (Treg) cells remains largely unexplored. Our aims were to characterize Foxp3(+) Treg-cell activation in a murine intravenous challenge model of disseminated C. albicans infection, and determine the contribution to disease. Flow cytometric analyses demonstrated that C. albicans infection drove in vivo expansion of a splenic CD4(+) Foxp3(+) population that correlated positively with fungal burden. Depletion from Foxp3(hCD2) reporter mice in vivo confirmed that Foxp3(+) cells exacerbated fungal burden and inflammatory renal disease. The CD4(+) Foxp3(+) population expanded further after in vitro stimulation with C. albicans antigens (Ags), and included at least three cell types. These arose from proliferation of the natural Treg-cell subset, together with conversion of Foxp3(-) cells to the induced Treg-cell form, and to a cell type sharing effector Th17-cell characteristics, expressing ROR-γt, and secreting IL-17A. The expanded Foxp3(+) T cells inhibited Th1 and Th2 responses, but enhanced Th17-cell responses to C. albicans Ags in vitro, and in vivo depletion confirmed their ability to enhance the Th17-cell response. These data lead to a model for disseminated candidiasis whereby expansion of Foxp3(+) T cells promotes Th17-cell responses that drive pathology.
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, UK; Aberdeen Fungal Group, University of Aberdeen, Aberdeen, UK; Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Whibley
authors.forename: Donna M
authors.initials: DM
authors.lastname: Maccallum
authors.forename: Mark A
authors.initials: MA
authors.lastname: Vickers
authors.forename: Sadia
authors.initials: S
authors.lastname: Zafreen
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
authors.forename: Shohei
authors.initials: S
authors.lastname: Hori
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.forename: Robert N
authors.initials: RN
authors.lastname: Barker
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hall
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000276:immunology* / Q000502:physiology; D002177:Candidiasis / Q000276:immunology* / Q000382:microbiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D007674:Kidney Diseases / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit
keywords: Candida albicans; Disseminated infection; Foxp3; Regulatory T (Treg) cell; Th17