Transcriptional Basis of Mouse and Human Dendritic Cell Heterogeneity

Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer. [Display omitted] •Single-cell analyses reveal novel dendritic cell subsets•Major cDC2 subsets differentially express T-bet and RORγt•Distinct pro- and anti-inflammatory potential of T-bet+ and Tbet– cDC2s•Transcriptional basis for cDC2 heterogeneity conserved across mouse and human Single-cell analyses of dendritic cells reveals new subsets with distinct pro- and anti-inflammatory potential.