Hamsa Narasimhan, Maria L. Richter, Ramin Shakiba, Nikos E. Papaioannou, Christina Stehle, Kaushikk Ravi Rengarajan, Isabel Ulmert, Arek Kendirli, Clara de la Rosa, Pin-Yu Kuo, Abigail Altman, Philipp Münch, Saba Mahboubi, Vanessa Küntzel, Amina Sayed, Eva-Lena Stange, Jonas Pes, Alina Ulezko Antonova, Carlos-Filipe Pereira, Ludger Klein, Diana Dudziak, Marco Colonna, Natalia Torow, Mathias W. Hornef, Björn E. Clausen, Martin Kerschensteiner, Katharina Lahl, Chiara Romagnani, Maria Colomé-Tatché, and Barbara U. Schraml
Significance
Antigen-presenting cells (APCs) orchestrate T cell immunity. Retinoic acid receptor-related orphan receptor-γt (RORγt)-expressing APCs are heterogenous regulators of T cell tolerance but their subtypes and lineage relationships are ill-defined. We report that RORγt+ dendritic cells (DCs) are evolutionarily conserved, exhibit wide tissue distribution and reconcile various RORγt+ APC populations known to promote peripheral T cell tolerance. We show that RORγt+ DCs can sense pathogens, migrate to lymph nodes, activate naïve CD4+ T cells, and accumulate in demyelinating neuroinflammation with a proinflammatory phenotype. Thus, RORγt+ DCs have a broad functional spectrum ranging from inducing T cell tolerance to T cell activation depending on signals they integrate from their environment. This highlights their therapeutic potential and their affiliation with DCs.
Abstract
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 the 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 proinflammatory 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 inducing peripheral T cell tolerance to T cell activation depending on signals they integrate from their environment.
