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

Candida albicans remains the fungus most frequently associated with nosocomial blood-stream infection. In disseminated candidiasis, the role of Foxp3+ regulatory T (Treg) cells remains largely unexplored. Our aims were to characterize Foxp3+ Treg-cell acti-vation 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 Foxp3hCD2 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 dissem