AUTHOR=Bhaskaran Natarajan , Faddoul Fady , Paes da Silva Andre , Jayaraman Sangeetha , Schneider Elizabeth , Mamileti Prerna , Weinberg Aaron , Pandiyan Pushpa TITLE=IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging JOURNAL=Frontiers in Immunology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.595936 DOI=10.3389/fimmu.2020.595936 ISSN=1664-3224 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_reg17) and an increase in dysfunctional IFN-γ⁺/Foxp3⁺ cells (T_regIFN-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_reg17 cells. In the absence of IL-1 receptor signaling, T_reg17 cells were reduced, but IL-6-driven expansion of T_regIFN-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^highT_reg17 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.