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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.

Original publication

DOI

10.1002/eji.201343604

Type

Journal article

Journal

Eur J Immunol

Publication Date

04/2014

Volume

44

Pages

1069 - 1083

Keywords

Candida albicans, Disseminated infection, Foxp3, Regulatory T (Treg) cell, Th17, Animals, Candida albicans, Candidiasis, Cell Proliferation, Cells, Cultured, Cytokines, Flow Cytometry, Forkhead Transcription Factors, Host-Pathogen Interactions, Interleukin-2 Receptor alpha Subunit, Kidney Diseases, Mice, Mice, Inbred C57BL, Spleen, T-Lymphocytes, Regulatory, Th17 Cells