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

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 reg 17) and an increase in dysfunctional IFN-g + /Foxp3 + cells (T reg IFN-g) in infected mice. Failure of MyD88-/-T regs to regulate effector CD4 + T cell functions correlated with heightened levels of IFN-g in CD4 + T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa in vivo. Mechanistically, IL-1b/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-g 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-1b 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-1b/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.

The role of dectin-1 signaling in altering tumor immune microenvironment in the context of aging

“…Understanding these mechanisms will lead to new combinatorial strategies in the face of PD-1/PD-L1 blockade resistance, leading to improved patient outcomes. Having linked some of the immunosenescent cytokines in T reg accrual and aging previously [26], here we show that the Dectin-1 signaling is required for increases in IL-1β, MDSC, and T regs during carcinogenesis, which is further enhanced in aged mice contributing to acceleration in tumor development in them.…”

“…2B ). This was significantly higher than what is found in gingival mucosa of healthy individuals (*P<0.05)[26]. Among CD45 + cells, there were also higher proportions of CD14 neg CD11B + CD33 + MDSC cells ( Fig.…”

“…Previous evidence has also shown that oral carriage of Candida is higher in elderly individuals and patients with OSCC[42-46]. We and others have previously shown that Candida infection can also induce IL-1β expression and T reg infiltration in oral mucosa[26; 47]. Because aforementioned results showed IL-1β was positively linked with tumorigenesis, we hypothesized that Candida infection and consequent IL-1β induction might worsen OSCC outcome.…”

“…2D ). Because IL-1β signaling is critical for induction of immunomodulatory ROR-γt + FOXP3 + cells in oral mucosal tissues and is implicated in oral tumor progression[26; 28; 29], we examined the expression of IL-1β. IL-1β was significantly increased in the supernatants derived from human tumors and resected tumor supernatants ( Fig.…”

“…Some of these FOXP3 + cells may also be critical for tissue repair or become dysfunctional depending on the inflammatory cytokine milieu[32]. Indeed we[26; 33-37] and others have shown distinct functions of T-bet + Foxp3 + cells, ROR-γt + Foxp3 + cells, and PD-1 + Foxp3 + cells, whose functions are significantly altered by cytokines including IL-6 and IL-1β in an mTOR dependent manner in oral mucosa[26]. Because CD25, PD-1, T-bet, ROR-γt, Suppression of Tumorigenicity 2 (ST-2) expression were all implicated in determining intra-tumoral T reg functions positively and negatively in other tissues[7; 28; 38; 39], we examined the expression of the molecules, comparing aged and young T regs , 16 weeks after 4-NQO administration.…”