Abstract
Age-associated T cell dysfunction is a defining feature of inflammaging and immunosenescence, the progressive decline in immune competence observed with advancing age. Here we identified the association between aging (defined as age >60) and fungal dysbiosis, notably characterized by increased colonization of Candida species in the oral mucosa. There is also a notable enrichment of other taxa related to the order Saccharomycetales in older individuals. In contrast, younger individuals exhibit a greater abundance of Cryptococcus, Yarrowia, Kluyveromyces, and various Incertae sedis lineages. Further analysis, stratified by HIV status, shows that older individuals in both healthy and HIV+ groups display significantly higher levels of Candida. Gingival tissues reveal that both healthy older group and HIV-positive group exhibit elevated levels of CD4(+)FOXP3(+) regulatory T cells (T(regs)) along with increased salivary concentrations of soluble TLR-2 and IL-6 compared to younger healthy group. Importantly, the abundance of Candida is positively correlated with elevated levels of mucosal T(regs), dysfunctional T(regs) (T(regDys)), and hyperactivated CD4(+) T cells. In vitro experiments provided mechanistic insights by further demonstrating that Candida can induce both proliferation and dysfunction of T(regs) in an IL-6 dependent manner, supporting the notion that Candida plays a role in oral T cell senescence and inflammaging. Collectively, these findings underscore a direct relationship between the commensal mycobiome and T(reg) population, which normally promotes mucosal homeostasis but becomes susceptible to dysfunction with aging.