防御と攻撃の切り替え – 二重の役割を持つ免疫細胞(Switching between defense and attack – immune cells with dual role)

2025-02-25 ミュンヘン大学(LMU)

<関連情報>

• https://www.lmu.de/en/newsroom/news-overview/news/switching-between-defense-and-attack-immune-cells-with-dual-role.html
• https://www.pnas.org/doi/10.1073/pnas.2417308122

RORγt発現樹状細胞は機能的に多様で進化的に保存された抗原提示細胞である RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells

Hamsa Narasimhan, Maria L. Richter, Ramin Shakiba, +26, and Barbara U. Schraml
Proceedings of the National Academy of Sciences  Published:February 24, 2025
DOI:https://doi.org/10.1073/pnas.2417308122

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.