Cross-species analyses reveal RORγt-expressing dendritic cells are a lineage of antigen presenting cells conserved across tissues

Abstract

Conventional dendritic cells (cDCs) are potent antigen presenting cells (APCs) that exhibit tissue and age-specific diversity allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination and cancer. Here, we resolve conflicting data about expression of retinoic acid receptor-related orphan receptor-γt (RORγt) in cDCs. We show that RORγt+ DCs exist in murine lymphoid and non-lymphoid tissues across age. Fate mapping, functional assays and single cell multiomic profiling reveal these cells as ontogenetically and transcriptionally distinct from other well characterized cDC subtypes, as well as from RORγt+ type 3 innate lymphocytes (ILC3s). We show that RORγt+ DCs can migrate to lymph nodes and activate naive CD4+ T cells in response to inflammatory triggers. Comparative and cross-species transcriptomics revealed homologous populations in human spleen, lymph nodes and intestines. Further, integrated meta-analyses aligned RORγt+ DCs identified here with other emerging populations of RORγt+APCs, including R-DC-like cells, Janus cells/extrathymic Aire expressing cells (eTACs) and subtypes of Thetis cells. While RORγt+APCs have primarily been linked to T cell tolerance, our work establishes RORγt+ DCs as unique lineage of immune sentinel cells conserved across tissues and species that expands the functional repertoire of RORγt+ APCs beyond promoting tolerance.