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

Narasimhan, Hamsa; Richter, Maria L.; Shakiba, Ramin; Papaioannou, Nikos E.; Stehle, Christina; Ravi Rengarajan, Kaushikk; Ulmert, Isabel; Kendirli, Arek ; Rosa, Clara de la; Kuo, Pin-Yu; Altman, Abigail ; Münch, Philipp ; Mahboubi, Saba ; Küntzel, Vanessa; Sayed, Amina; Stange, Eva-Lena ; Pes, Jonas; Ulezko Antonova, Alina; Pereira, Carlos-Filipe ; Klein, Ludger; Dudziak, Diana ; Colonna, Marco ; Torow, Natalia ; Hornef, Mathias W. ; Clausen, Björn E. ; Kerschensteiner, Martin ; Lahl, Katharina; Romagnani, Chiara; Colomé-Tatché, Maria und Schraml, Barbara U. (2025): RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells. In: Proceedings of the National Academy of Sciences, Vol. 122, No. 9, e2417308122

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.

• Item Type: Journal article
• Faculties: Medicine; Medicine > Institute for Immunology; Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Medical Center of the University of Munich > Neurological Clinic and Polyclinic with Friedrich Baur Institute
• Research Centers: Graduate School of Systemic Neurosciences (GSN)
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0027-8424
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198