title: IL-10 distinguishes a unique population of activated, effector-like CD8+T cells in murine acute liver inflammation.
abstract: Immune-mediated liver injury is a central feature of hyperinflammatory diseases, such as hemophagocytic syndromes, yet the immunologic mechanisms underlying those processes are incompletely understood. In this study, we used the toll-like receptor 9 (TLR9)-mediated model of a hemophagocytic syndrome known as macrophage activation syndrome (MAS) to dissect the predominant immune cell populations infiltrating the liver during inflammation. We identified CD8+T cells that unexpectedly produce interleukin-10 (IL-10) in addition to interferon-γ (IFN-γ) as a major hepatic population induced by TLR9 stimulation. Despite their ability to produce this anti-inflammatory cytokine, IL-10+hepatic CD8+T cells in TLR9-MAS mice did not resemble CD8+T suppressor cells. Instead, the induction of these cells occurred independently of antigen stimulation and was partially dependent on IFN-γ. IL-10+hepatic CD8+T cells demonstrated an activated phenotype and high turnover rate, consistent with an effector-like identity. Transcriptional analysis of this population confirmed a gene signature of effector CD8+T cells yet suggested responsiveness to liver injury-associated growth factors. Together, these findings suggest that IL-10+CD8+T cells induced by systemic inflammation to infiltrate the liver have initiated an inflammatory, rather than regulatory, program and may thus have a pathogenic role in severe, acute hepatitis.
authors.affiliation: Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rood
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; and.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Canna
authors.affiliation: Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Lehn K
authors.initials: LK
authors.lastname: Weaver
authors.affiliation: Molecular Profiling Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Tobias
authors.affiliation: Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; behrens@email.chop.edu.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
mesh_terms: D000208:Acute Disease; D000818:Animals; D000941:Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D008099:Liver / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051359:Lymphohistiocytosis, Hemophagocytic / Q000276:immunology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D010641:Phenotype; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000941:Antigens; D036341:Intercellular Signaling Peptides and Proteins; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: cytokine; hemophagocytic syndrome; hepatitis