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 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 disseminated candidiasis whereby expansion of Foxp3+ T cells promotes Th17-cell responses that drive pathology.
Highlights
Fungi are a major cause of nosocomial bloodstream infection, in critically ill patients receiving antibiotics, immunosuppressive treatments or who have undergone surgery [1, 2]
We report that C. albicans drives expansion of a complex Foxp3+ T-cell population, which is detrimental to the host, since its numbers correlate with fungal burden, and selective depletion in vivo ameliorated pathology
This work demonstrates, for the first time, that disseminated infection with C. albicans drives the expansion of complex Foxp3+ cell populations, including cells with Natural Treg (nTreg), induced Treg (iTreg), and Th17-cell characteristics
Summary
Fungi are a major cause of nosocomial bloodstream infection, in critically ill patients receiving antibiotics, immunosuppressive treatments or who have undergone surgery [1, 2]. C. albicans induces innate and adaptive immune responses, mortality rates remain high and a better understanding of factors limiting protective immunity will be critical for the development of more effective therapies [1, 3]. One such factor may be the balance between host CD4+ T effector (Teff) and regulatory T (Treg)-cell responses. An excessive inflammatory response induced by Th17 cells in mice may cause immune pathology associated with C. albicans survival and dissemination [7,8,9]
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