Enrichment of Candida associated with dysbiosis contributes to mucosal CD4+FOXP3+ regulatory T cell accrual and their dysfunction in aging

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.