Candidalysin induces Tim-3 expression in macrophages to suppress antifungal immunity in oropharyngeal candidiasis.

Oropharyngeal candidiasis significantly impacts patients' quality of life. Although the immune mechanisms underlying OPC have been explored, the roles of immune checkpoints and macrophages in this context remain unclear. We employed single-cell techniques to analyze changes in the oral immune microenvironment and explored the role of Tim-3 in OPC. Our single-cell analysis identified distinct macrophage subpopulations in OPC tissue, each exhibiting heterogeneous antifungal immune responses. Further investigation revealed that candidalysin induces Tim-3, which primarily reduces the proportion of macrophage subpopulations 1 and 2 in OPCs. Additionally, it suppresses the inflammatory response during infection. Experimental research showed that Tim-3 inhibited the P65 inflammatory signaling pathway in macrophages, thereby reducing the secretion of inflammatory cytokines such as l1b, Il6, Tnf, Il23, and chemokines including Ccl2, Cxcl1, Cxcl2, Cxcl3, and Cxcl5. Additionally, Tim-3 promoted macrophage apoptosis, potentially contributing to the decreased proportion of macrophages. We also found that Tim-3 suppressed the phagocytic and killing functions of macrophages against C.albicans. Notably, our research revealed that Tim-3's ligand, Galectin-9, also exhibits functional similarities to Tim-3. Specifically, the Galectin-9 gene, Lgals9, is also induced by candidalysin. This study identifies candidalysin in inhibiting macrophage responses to C.albicans through the induction of Galectin-9/Tim-3 in oral mucosal immunity, potentially representing a novel mechanism of immune evasion by C.albicans in OPC. Therefore, our research provides a basis for considering this axis as a potential therapeutic target.