An immunobiliary single-cell atlas resolves crosstalk between type 2 conventional dendritic cells and γδ T cells in cholangitis

Abstract

Abstract 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 γδ T cells inducing an Il17 response (γδ T17). Dissection of the cDC2B-γδ 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 γδ T17 responses in cholestatic liver injury, and liver fibrosis was reduced in a model of inducible γδ 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 γδ T cells contingent on the induction by peribiliary cDC2B, highlighting relevant disease determinants within the immunobiliary and liver-draining LN niche.