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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.

IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging