Abstract
CD4+Foxp3+Tregs maintain immune homeostasis, but distinct mechanisms underlying their functional heterogeneity during infections are driven by specific cytokine milieu. Here we show that MyD88 deletion in Foxp3+ cells altered their function and resulted in increased fungal burden and immunopathology during oral Candida albicans (CA) challenge. Excessive inflammation due to the absence of MyD88 in Tregs coincided with a reduction of the unique population of IL-17A expressing Foxp3+ cells (Treg17) and an increase in dysfunctional IFN-γ+/Foxp3+ cells (TregIFN-γ) in infected mice. Failure of MyD88-/- Tregs to regulate effector CD4+ T cell functions correlated with heightened levels of IFN-γ in CD4+ T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa in vivo. Mechanistically, IL-1β/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of Treg17 cells. In the absence of IL-1 receptor signaling, Treg17 cells were reduced, but IL-6-driven expansion of TregIFN-γ cells was increased. This mechanism was physiologically relevant during Candida infection in aged mice, as they exhibited IL-1 receptor/MyD88 defect in Foxp3+ cells, loss of p-mTORhighTreg17 cells and reduced levels of IL-1β in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with Treg dysfunction, aging was associated with increased CD4+ T cell hyperactivation and heightened levels of IL-6 in mice and humans in oral mucosa in vivo. Taken together, our data identify IL-1β/MyD88/Treg axis as a new component that modulates inflammatory responses in oral mucosa. Also, dysregulation of this axis in an aging immune system may skew host defense towards an immunopathological response in mucosal compartments.
Highlights
CD4+CD25+Foxp3+ regulatory T cells (Tregs) are central in controlling the magnitude of an immune response thereby regulating autoimmunity and maintaining mucosal tolerance [1]
We show that IL-1b/myeloid differentiation primary response 88 (MyD88) principally promotes the induction and proliferation of RORgt+IL17+Foxp3+ cells (Treg17) in an mTOR dependent manner during Candida challenge
We employed this in vitro cell culture system because: 1) We have previously found that Heat killed Candida albicans germ tubes (HKGT) can cause in vitro proliferation of Tregs in TLR2 dependent manner; 2) TGF-b1 is important for survival of Foxp3+Tregs during oral Candida albicans (CA) infection as well resistance to Candida in vivo [2, 32, 33]; and 3) Activating T cells in a whole tissue culture system including the local antigen presenting cells (APC) is more physiological than using purified T cell cultures because APC secrete appropriate cytokines in the milieu [2, 32]
Summary
CD4+CD25+Foxp3+ regulatory T cells (Tregs) are central in controlling the magnitude of an immune response thereby regulating autoimmunity and maintaining mucosal tolerance [1]. We show that IL-1b/MyD88 principally promotes the induction and proliferation of RORgt+IL17+Foxp3+ cells (Treg17) in an mTOR dependent manner during Candida challenge. These cells are required for optimal resolution of infection and inflammation. While RORgt expressing Foxp3+ cells have been implicated in playing diverse roles in intestinal inflammation [13, 24, 25], our results demonstrate their immune-protective functions and the contrasting roles of IL-1b and IL-6 in determining their plasticity and function during an oral mucosa infection. Our data highlight an age dependent dysregulation of this mechanism due to an imbalance in these cytokines These results demonstrate that IL-1b/MyD88 signaling augments Treg functions and modulates mucosal immunity and provide
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