RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen presenting cells

Conventional dendritic cells (cDCs) are potent antigen presenting cells (APCs) that integrate signals from their environment allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination, autoimmunity and cancer. Here, we use fate mapping, functional analyses and comparative cross-species transcriptomics to show that RORγt+ DCs are a conserved, functionally versatile and transcriptionally distinct type of DCs. RORγt+ DCs entail various populations described in different contexts including Janus cells/RORγt-expressing extrathymic Aire expressing cells (eTACs), subtypes of Thetis cells, RORγt+ DC (R-DC) like cells, cDC2C and ACY3+ DCs. We show that in response to inflammatory triggers RORγt+ DCs can migrate to lymph nodes and in spleen can activate naïve CD4+ T cells. These findings expand the functional repertoire of RORγt+ DCs beyond the known role of eTACs and Thetis cells in inducing T cell tolerance to self-antigens and intestinal microbes in mice. We further show that RORγt+ DCs with pro-inflammatory features accumulate in autoimmune neuroinflammation in mice and men. Thus, our work establishes RORγt+ DCs as immune sentinel cells that exhibit a broad functional spectrum ranging from T cell tolerance to T cell activation depending on signals they integrate from their environment.