CXCR3 deficiency exacerbates liver disease and abrogates tolerance in a mouse model of immune-mediated hepatitis.

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.