Divergent Immunomodulatory Roles of Fungal DNA in Shaping Treg and Inflammatory Responses

Fungal communities in the gut influence host immunity, yet most studies have focused on cell wall components rather than genetic materials. Here, we explore how fungal genomic DNA (gDNA) from <i>Candida albicans</i>, <i>Saccharomyces cerevisiae</i>, and <i>Cryptococcus neoformans</i> modulate immune responses in human CD4⁺ T cells, murine splenocytes, and THP-1-derived macrophages. We find that <i>C. albicans</i> gDNA promotes the development of regulatory T cells and increases IL-10, fostering immune tolerance and preserving CD4⁺ T cell viability in an inflammatory setting. <i>S. cerevisiae</i> gDNA induces moderate Treg responses with restrained effector T cell expansion and higher checkpoint gene expression, entirely consistent with its commensal nature. In contrast, <i>C. neoformans</i> gDNA elicits a strongly inflammatory profile, promoting Th1/Th17 cells and driving high cytokine production. Mechanistically, <i>C. albicans</i> and <i>S. cerevisiae</i> gDNA dampen DNA-sensing pathways and enhance immune checkpoint molecules that act as brakes against overactivation, while <i>C. neoformans</i> gDNA robustly activates innate sensing pathways with limited checkpoint induction. These species-specific signaling profiles reveal that fungal gDNA itself can influence whether the immune system adopts a tolerant or inflammatory response toward fungi. This discovery highlights fungal genomic DNA as a previously underappreciated regulator of host-fungus interactions, offering new insight into commensal persistence, pathogenic invasion, and the potential for DNA-based antifungal interventions.