Expansion of Foxp3+ T‐cell populations by Candida albicans enhances both Th17‐cell responses and fungal dissemination after intravenous challenge. Issue 4 (13th February 2014)

• Record Type: Journal Article
• Authors: Whibley, Natasha; MacCallum, Donna M.; Vickers, Mark A.; Zafreen, Sadia; Waldmann, Herman; Hori, Shohei; Gaffen, Sarah L.; Gow, Neil A. R.; Barker, Robert N.; Hall, Andrew M.
• Is Part Of: European journal of immunology. Volume 44:Issue 4(2014:Apr.)
• Page Start: 1069
• Page End: 1083
• Publication Date: 2014-02-13
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201343604
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <italic>Candida albicans</italic> remains the fungus most frequently associated with nosocomial bloodstream infection. In disseminated candidiasis, the role of Foxp3<sup>+</sup> regulatory T (Treg) cells remains largely unexplored. Our aims were to characterize Foxp3<sup>+</sup> Treg‐cell activation in a murine intravenous challenge model of disseminated <italic>C. albicans</italic> infection, and determine the contribution to disease. Flow cytometric analyses demonstrated that <italic>C. albicans</italic> infection drove in vivo expansion of a splenic CD4<sup>+</sup>Foxp3<sup>+</sup> population that correlated positively with fungal burden. Depletion from Foxp3<sup>hCD2</sup> reporter mice in vivo confirmed that Foxp3<sup>+</sup> cells exacerbated fungal burden and inflammatory renal disease. The CD4<sup>+</sup>Foxp3<sup>+</sup> population expanded further after in vitro stimulation with <italic>C. albicans</italic> antigens (Ags), and included at least three cell types. These arose from proliferation of the natural Treg‐cell subset, together with conversion of Foxp3<sup>−</sup> 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<sup>+</sup> T cells inhibited Th1 and Th2 responses, but enhanced Th17‐cell responses to <italic>C. albicans</italic> 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<sup>+</sup> T cells promotes Th17‐cell responses that drive pathology.</p> </abstract>