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.

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (T_regDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the T_regDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal T_regDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and T_reg dysfunction.

Candida albicans is a commensal fungus that asymptomatically colonizes the skin and mucosa of 60% of healthy individuals. Breaches in the cutaneous and mucosal barriers trigger candidiasis that ranges from asymptomatic candidemia and mucosal infections to fulminant sepsis with 70% mortality rates. Fungi influence at least several diseases, in part by mechanisms such as the production of pro-carcinogenic agents, molecular mimicking, and triggering of the inflammation cascade. These processes impact the interactions among human pathogenic and resident fungi, the bacteriome in various organs/tissues, and the host immune system, dictating the outcomes of invasive infections, metabolic diseases, and cancer. Although mechanistic investigations are at stages of infancy, recent studies have advanced our understanding of host–fungal interactions, their role in immune homeostasis, and their associated pathologies. This review summarizes the role of C. albicans and other opportunistic fungi, specifically their association with various diseases, providing a glimpse at the recent developments and our current knowledge in the context of inflammatory-bowel disease (IBD), cancers, and COVID-19. Two of the most common human diseases where fungal interactions have been previously well-studied are cancer and IBD. Here we also discuss the emerging role of fungi in the ongoing and evolving pandemic of COVID-19, as it is relevant to current health affairs.