Abstract
CD4(+)Foxp3(+)T(regs) 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 T(regs) coincided with a reduction of the unique population of IL-17A expressing Foxp3(+) cells (T(reg)17) and an increase in dysfunctional IFN-γ(+)/Foxp3(+) cells (T(reg)IFN-γ) in infected mice. Failure of MyD88(-/-) T(regs) 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 T(reg)17 cells. In the absence of IL-1 receptor signaling, T(reg)17 cells were reduced, but IL-6-driven expansion of T(reg)IFN-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-mTOR(high)T(reg)17 cells and reduced levels of IL-1β in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with T(reg) 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/T(reg) 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.