Resident cDC2 subset drive CD4+ T-cell help-independent CD8+ T cell cross-priming for type 17-mediated fungal vaccine immunity 2255958

Abstract Introduction The global rise in invasive fungal infections, mainly in immunocompromised populations, underscores the urgent need for effective fungal vaccines. Accumulating evidence suggests that T cells are instrumental in providing fungal immunity. Dendritic cells (DCs) are essential sentinels that bridge innate with adaptive immunity, orchestrating T-cell activation and dictating vaccine immunity. Since CD4+ T cell help is known to license DC for CD8+ T cell cross-priming and our publications showing its dispensability for inducing sterilizing antifungal vaccine immunity, the nature of DC activation in CD4+ lymphopenia is unclear. Methods Using a murine model of fungal vaccination, we delineated the dynamics, kinetics, transcriptional profile, and cross-presentation of DC subsets in draining lymph nodes of immunocompromised hosts using flow cytometry and bulk RNA-Sequencing. Results Vaccination with experimental attenuated fungal strains elicited dominant cDC2 responses over cDC1 in draining lymph nodes, independent of CD4+ T cells. Transcriptomic profiling of sorted DC subsets revealed that cDC2 possessed an enriched inflammatory and chemokine-signaling signature, whereas cDC1 exhibited programs associated with growth and interleukin signaling. Notably, resident cDC2 expressed a regulatory costimulatory profile, whereas migratory cDC2 exhibited a pro-inflammatory gene signature. Functionally, resident cDC2 showed superior antigen processing, cross-presentation, and type 17-polarizing cytokine gene expression profile compared with migratory cDC2 or cDC1. Conclusion Collectively, these findings identify cDC2 as the principal cross-presenting subset driving antifungal vaccine immunity through type 17-biased CD8+ T cell programming. By defining the molecular and functional landscape of DC subset specialization, our study provides mechanistic insight for the rational, next-generation adjuvanted fungal vaccines optimized for immunocompromised hosts. Funding Source NIH-NIAID R01AI153522 (to SGN) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)