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

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.

Adaptive immune responses toCandida albicansinfection

“…C Treg cells were observed to induce Th17 responses, albeit to the detriment of the host. 83 In contrast to these findings is the observation that Treg cells consume IL-2 (thereby preventing IL-2-mediated inhibition of Th17 polarization), assisting the generation of protective Th17 responses mounted during murine OPC. 84 Clearly, the roles(s) played by Treg cells in response to C. albicans infection have yet to be characterized in full.…”

Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells

“…However, under inflammatory Th17 conditions, when nT regs are stimulated with TLR-2 ligands in the presence of APC, IL-6, IL-23 and IL-1β, a minor fraction (<20%) of nT regs lose Foxp3. Interestingly, among nT regs that do not lose Foxp3, TLR-2 ligands also induce proliferation and IL-17A production [12,78]. Importantly, when mice are infected with a TLR-2 activating fungus, C. albicans , Foxp3 + cells expand and produce IL-17A in vivo [12,78].…”

“…Interestingly, among nT regs that do not lose Foxp3, TLR-2 ligands also induce proliferation and IL-17A production [12,78]. Importantly, when mice are infected with a TLR-2 activating fungus, C. albicans , Foxp3 + cells expand and produce IL-17A in vivo [12,78]. Myd88 [148] [129,138] and TLR-2 are required, both in T regs and APC for Foxp3+ cells to produce IL-17A [78].…”

Regulatory T-cell: Regulator of Host Defense in Infection

“…However, the presence of regulatory T-cells inhibits clearance of C. albicans with macrophages. Contrary to , other studies administrated that in C. albicans involvements , elevated percentage of Treg cells correlated to protection from infection, as in some autoimmune diseases with faulty regulatory Tcells, mucocutaneous candidiasis were observed (Whibley et al, 2014). …”