title: Liver restores immune homeostasis after local inflammation despite the presence of autoreactive T cells.
abstract: The liver must keep equilibrium between immune tolerance and immunity in order to protect itself from pathogens while maintaining tolerance to food antigens. An imbalance between these two states could result in an inflammatory liver disease. The aims of this study were to identify factors responsible for a break of tolerance and characterize the subsequent restoration of liver immune homeostasis. A pro-inflammatory environment was created in the liver by the co-administration of TLR ligands CpG and Poly(I:C) in presence or absence of activated liver-specific autoreactive CD8(+) T cells. Regardless of autoreactive CD8(+) T cells, mice injected with CpG and Poly(I:C) showed elevated serum ALT levels and a transient liver inflammation. Both CpG/Poly(I:C) and autoreactive CD8(+)T cells induced expression of TLR9 and INF-γ by the liver, and an up-regulation of homing and adhesion molecules CXCL9, CXCL10, CXCL16, ICAM-1 and VCAM-1. Transferred CFSE-labeled autoreactive CD8(+) T cells, in presence of TLR3 and 9 ligands, were recruited by the liver and spleen and proliferated. This population then contracted by apoptosis through intrinsic and extrinsic pathways. Up-regulation of FasL and PD-L1 in the liver was observed. In conclusion, TLR-mediated activation of the innate immune system results in a pro-inflammatory environment that promotes the recruitment of lymphocytes resulting in bystander hepatitis. Despite this pro-inflammatory environment, the presence of autoreactive CD8(+) T cells is not sufficient to sustain an autoimmune response against the liver and immune homeostasis is rapidly restored through the apoptosis of T cells.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Quebec, Canada.
authors.forename: Kathie
authors.initials: K
authors.lastname: Béland
authors.forename: Pascal
authors.initials: P
authors.lastname: Lapierre
authors.forename: Idriss
authors.initials: I
authors.lastname: Djilali-Saiah
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D015153:Blotting, Western; D018826:CD13 Antigens / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry; D006706:Homeostasis / Q000502:physiology; D007113:Immunity, Innate; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D054357:Chemokine CXCL10; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D054370:Chemokine CXCL9; C498926:Cxcl16 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D018826:CD13 Antigens