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Narasimhan, Hamsa; Richter, Maria L.; Shakiba, Ramin; Papaioannou, Nikos E.; Stehle, Christina; Ravi Rengarajan, Kaushikk; Ulmert, Isabel; Kendirli, Arek ORCID logoORCID: https://orcid.org/0000-0001-6888-9131; Rosa, Clara de la; Kuo, Pin-Yu; Altman, Abigail ORCID logoORCID: https://orcid.org/0009-0002-9692-2976; Münch, Philipp ORCID logoORCID: https://orcid.org/0009-0004-1289-6833; Mahboubi, Saba ORCID logoORCID: https://orcid.org/0000-0001-9029-8784; Küntzel, Vanessa; Sayed, Amina; Stange, Eva-Lena ORCID logoORCID: https://orcid.org/0000-0001-8277-0663; Pes, Jonas; Ulezko Antonova, Alina; Pereira, Carlos-Filipe ORCID logoORCID: https://orcid.org/0000-0002-9724-1382; Klein, Ludger; Dudziak, Diana ORCID logoORCID: https://orcid.org/0000-0001-9358-134X; Colonna, Marco ORCID logoORCID: https://orcid.org/0000-0001-5222-4987; Torow, Natalia ORCID logoORCID: https://orcid.org/0000-0003-3013-8724; Hornef, Mathias W. ORCID logoORCID: https://orcid.org/0000-0001-6096-9110; Clausen, Björn E. ORCID logoORCID: https://orcid.org/0000-0002-2484-7842; Kerschensteiner, Martin ORCID logoORCID: https://orcid.org/0000-0003-4898-9383; Lahl, Katharina; Romagnani, Chiara; Colomé-Tatché, Maria ORCID logoORCID: https://orcid.org/0000-0002-2224-7560 und Schraml, Barbara U. ORCID logoORCID: https://orcid.org/0000-0002-5801-0151 (2025): RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells. In: Proceedings of the National Academy of Sciences, Bd. 122, Nr. 9, e2417308122 [PDF, 7MB]

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.

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