Expansion of Foxp3+ T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge

Natasha Whibley, Donna M Maccallum, Mark A Vickers, Sadia Zafreen, Herman Waldmann, Shohei Hori, Sarah L Gaffen, Neil A R Gow, Robert N Barker, Andrew M Hall

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Abstract

Candida albicans remains the fungus most frequently associated with nosocomial bloodstream infection. In disseminated candidiasis, the role of Foxp3(+) regulatory T (Treg) cells remain 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, 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 antigens 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. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)1069-1083
Number of pages15
JournalEuropean Journal of Immunology
Volume44
Issue number4
Early online date13 Feb 2014
DOIs
Publication statusPublished - Apr 2014

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Keywords

  • Candida albicans
  • disseminated infection
  • FoxP3
  • regulatory T (Treg) cell
  • Th17

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