An immunobiliary single-cell atlas resolves crosstalk between type 2 conventional dendritic cells and ?d T cells in cholangitis [scRNA-seq]

The liver biliary niche serves as a reservoir of tissue-resident immune cells and supports tissue fibrosis upon damage, yet the role of peribiliary immune cells during cholangitis remains poorly understood. Here, we induce cholestatic liver injury mirroring human biliary diseases with bile acid retention in mice to establish a spatial and multimodal single-cell RNA sequencing atlas of the liver and liver-draining lymph nodes (LN). We characterized a hepatic disease state trajectory from dendritic cell precursors (preDCs) to a mature subset of pro-inflammatory Mgl2+ type 2 conventional dendritic cells (cDC2B) and observed dynamic crosstalk with ?d T cells inducing an Il17 response (?d T17). Dissection of the cDC2B-?d T cell communication node identified the Icosl-Icos pair as an important cell contact-dependent interaction, which was validated in vitro. In vivo, cDC2B depletion attenuated ?d T17 responses in cholestatic liver injury, and liver fibrosis was reduced in a model of inducible ?d T cell depletion and in an Il17-deficient background. Our work demonstrates dynamic turnover of cDC2 within the biliary niche during cholestasis, and a profibrogenic function of ?d T cells contingent on the induction by peribiliary cDC2B, highlighting relevant disease determinants within the immunobiliary and liver-draining LN niche. Overall design: Multimodal mouse and human scRNA seq data. 6 human liver samples to capture pseudonormal liver cells and identify niche interactions. Furthermore a DDC disease atlas consisting of 12 samples covering a control and 5 disease timepoints to analyse immune cell dynamics in the DDC model. Furthermore, scRNA-seq datasets covering inflammatory resolution after long-term DDC diet and a short term DDC diet in combination with a cDC2B depletion. A CITE-seq dataset from liver draining lymph nodes at a control and two disease timepoints for the analysis of cDC2 dynamics. Two experiments of liver immune cells capturing transcriptome and genomic accessibility data modalities at steady state and early cholestasis (DDC D5). Finally, multiplexed scRNA seq data of liver and lymph node derived ?d T cells undergoing cholestasis/cholestasis resolution and disease after cDC2B cell depletion.