IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17AFoxp3 Cells During Mucosal Infection and Is Dysregulated With Aging.

CD4Foxp3T 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 (CA) challenge. Excessive inflammation due to the absence of MyD88 in T coincided with a reduction of the unique population of IL-17A expressing Foxp3 cells (T17) and an increase in dysfunctional IFN-γ/Foxp3 cells (TIFN-γ) in infected mice. Failure of MyD88 T 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 . Mechanistically, IL-1β/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of T17 cells. In the absence of IL-1 receptor signaling, T17 cells were reduced, but IL-6-driven expansion of TIFN-γ cells was increased. This mechanism was physiologically relevant during infection in aged mice, as they exhibited IL-1 receptor/MyD88 defect in Foxp3 cells, loss of p-mTORT17 cells and reduced levels of IL-1β in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with T dysfunction, aging was associated with increased CD4 T cell hyperactivation and heightened levels of IL-6 in mice and humans in oral mucosa . Taken together, our data identify IL-1β/MyD88/T 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.