Abstract
IL-33 promotes type 2 immunity, epithelial repair, and tissue fibrosis by activating group 2 innate lymphoid cells (ILC2). ILC2 lack all known surface markers of mature T, B, NK, and myeloid cell lineages (Linneg), express the IL-33 receptor ST2, and release type 2 cytokines which contribute to cholangiocyte proliferation and activation of hepatic stellate cells. This pathway results in massive proliferation of the extrahepatic bile duct (EHBD) but also exacerbates liver fibrosis, suggesting that there may be tissue-specific subpopulations of IL-33-induced ILC. To determine the tissue-specific subsets of ILC in the hepatobiliary system, we analyzed CD45+Linneg mononuclear cells from IL-33 treated adult Balb/c mouse liver or EHBD by single cell RNA sequencing. Principal component analysis identified 6 major CD45+Linneg cell classes, two of which were restricted to the EHBD. One of these classes, biliary immature myeloid (BIM) cells, was predicted to interact with ILC2 by a network of shared receptor-ligand pairs. BIM highly expressed Gp49 and ST2 receptors on the cell surface while lacking surface expression of markers for mature myeloid cells. In conclusion, single cell RNA sequencing identified IL-33 responsive cell groups regionally confined to the liver or extrahepatic bile duct, including a novel population of CD45+Linneg Gp49-expressing mononuclear cells.
Highlights
Innate lymphoid cells (ILC) are distributed at epithelial sites early in life to uniquely respond to tissue injury and initiate and participate in immune responses
We investigated the heterogeneity of tissue-specific subclasses of hepatobiliary ILCs by performing single cell RNA sequencing on CD45+Linneg mononuclear cells isolated from the liver or extrahepatic bile duct (EHBD) after IL-33 administration
Based on the role of IL-33 in the activation of ILCs, we investigated how the functional maturation of ILCs is regulated by the tissue microenvironment in response to IL-33 by using single cell RNA sequencing of hepatic mononuclear cells
Summary
Innate lymphoid cells (ILC) are distributed at epithelial sites early in life to uniquely respond to tissue injury and initiate and participate in immune responses. ILC express CD45, IL-7Rα and other immune activation markers but lack all known lineage markers (Linneg) for T, B, myeloid, and NK cells [1,2,3]. Among ILCs, the group 2 innate lymphoid cells (ILC2) respond. Heterogeneity in IL-33 responsive hepatobiliary innate lymphoid cells funded in part by NIH DK064008 (to J.A.B) and NIH P30 DK078392 (awarded to the Digestive Diseases Health Center at Cincinnati Children’s Hospital Medical Center). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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