| First Author | Bhaskaran N | Year | 2020 |
| Journal | Front Immunol | Volume | 11 |
| Pages | 595936 | PubMed ID | 33240286 |
| Mgi Jnum | J:342991 | Mgi Id | MGI:6729527 |
| Doi | 10.3389/fimmu.2020.595936 | Citation | Bhaskaran N, et al. (2020) IL-1beta-MyD88-mTOR Axis Promotes Immune-Protective IL-17A(+)Foxp3(+) Cells During Mucosal Infection and Is Dysregulated With Aging. Front Immunol 11:595936 |
| abstractText | CD4(+)Foxp3(+)Tregs 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 Tregs coincided with a reduction of the unique population of IL-17A expressing Foxp3(+) cells (Treg17) and an increase in dysfunctional IFN-gamma(+)/Foxp3(+) cells (TregIFN-gamma) in infected mice. Failure of MyD88(-/-) Tregs to regulate effector CD4(+) T cell functions correlated with heightened levels of IFN-gamma in CD4(+) T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa in vivo. Mechanistically, IL-1beta/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of Treg17 cells. In the absence of IL-1 receptor signaling, Treg17 cells were reduced, but IL-6-driven expansion of TregIFN-gamma 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)Treg17 cells and reduced levels of IL-1beta in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with Treg 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-1beta/MyD88/Treg 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. |
