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

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.
(Copyright © 2020 Bhaskaran, Faddoul, Paes da Silva, Jayaraman, Schneider, Mamileti, Weinberg and Pandiyan.)