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

Abstract

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)