title: CXCR3 deficiency exacerbates liver disease and abrogates tolerance in a mouse model of immune-mediated hepatitis.
abstract: The chemokine receptor CXCR3 is preferentially expressed by Th1 cells and critically involved in their recruitment to inflamed tissue. In a mouse model of immune-mediated liver injury inducible by Con A, we investigated the role of CXCR3 in acute IFN-γ-mediated hepatitis as well as in tolerance induction, which has been shown to depend on IL-10-producing CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Induction of Con A hepatitis resulted in increased intrahepatic expression of the CXCR3 ligands CXCL9, CXCL10, and CXCL11. CXCR3(-/-) mice developed a more severe liver injury with higher plasma transaminase activities and a more pronounced Th1/Th17 response compared with wild-type (wt) animals upon Con A injection. Moreover, CXCR3(-/-) mice did not establish tolerance upon Con A restimulation, although Tregs from CXCR3(-/-) mice were still suppressive in an in vitro suppression assay. Instead, Tregs failed to accumulate in livers of CXCR3(-/-) mice upon Con A restimulation in contrast to those from wt animals. Con A-tolerant wt mice harbored significantly increased numbers of intrahepatic CXCR3(+)T-bet(+) Tregs that produced IL-10 compared with nontolerant animals. IFN-γ deficiency or anti-IFN-γ Ab treatment demonstrated that conversion to CXCR3(+)T-bet(+) Tregs depended on a Th1 response. Accordingly, in an immunotherapeutic approach, CD4(+)CD25(+)Foxp3(+) Tregs from Con A-pretreated CXCR3-deficient mice failed to protect against Con A-induced hepatitis, whereas Tregs from Con A-tolerant wt mice allowed CXCR3-deficient mice to recover from Con A hepatitis. In summary, CXCR3(+)T-bet(+)IL-10(+) Tregs are generated in the liver in dependence of IFN-γ, then disseminated into the organism and specifically migrate into the liver, where they limit immune-mediated liver damage.
authors: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Annette
authors: A
authors: Erhardt
authors: Claudia
authors: C
authors: Wegscheid
authors: Benjamin
authors: B
authors: Claass
authors: Antonella
authors: A
authors: Carambia
authors: Johannes
authors: J
authors: Herkel
authors: Hans-Willi
authors: HW
authors: Mittrücker
authors: Ulf
authors: U
authors: Panzer
authors: Gisa
authors: G
authors: Tiegs
mesh_terms: D000818:Animals; D002469:Cell Separation; D003208:Concanavalin A / Q000633:toxicity; D005434:Flow Cytometry; D006505:Hepatitis / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000633:toxicity; D054367:Receptors, CXCR3 / Q000172:deficiency* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C515188:Cxcr3 protein, mouse; D008934:Mitogens; D054367:Receptors, CXCR3; D003208:Concanavalin A; D007371:Interferon-gamma