Chemokine receptor CXCR3 deficiency exacerbates murine autoimmune cholangitis by promoting pathogenic CD8+ T cell activation

Abstract

CXC Chemokine Receptor 3 (CXCR3) is functionally pleiotropic and not only plays an important role in chemotaxis, but also participates in T cell differentiation and may play a critical role in inducing and maintaining immune tolerance. These observations are particularly critical for autoimmune cholangitis in which CXCR3 positive T cells are found around the portal areas of both humans and mouse models of primary biliary cholangitis (PBC). Herein, we investigated the role of CXCR3 in the pathogenesis of autoimmune cholangitis. We have taken advantage of a unique CXCR3 knockout dnTGFβRII mouse to focus on the role of CXCR3, both by direct observation of its influence on the natural course of disease, as well as through adoptive transfer studies into Rag−/− mice. We report herein that not only do CXCR3 deficient mice develop an exacerbation of autoimmune cholangitis associated with an expanded effector memory T cell number, but also selective adoptive transfer of CXCR3 deficient CD8+ T cells induces autoimmune cholangitis. In addition, gene microarray analysis of CXCR3 deficient CD8+ T cells reveal an intense pro-inflammatory profile. Our data suggests that the altered gene profiles induced by CXCR3 deficiency promotes autoimmune cholangitis through pathogenic CD8+ T cells. These data have significance for human PBC and other autoimmune liver diseases in which therapeutic intervention might be directed to chemokines and/or their receptors.

The CXC Chemokine Receptor 3 Inhibits Autoimmune Cholangitis via CD8+ T Cells but Promotes Colitis via CD4+ T Cells

“…Deletion of CXCR3 from the CD25 −/− mice resulted in aggravated hepatic inflammatory responses with increased CD8 + T cells associated with their increased production of inflammatory cytokine IFN-γ in the liver, but alleviated colitis with decreased CD4 + T cells associated with their reduced production of IL-17A in the colon. These results are in agreement with our previous findings on the different roles of IFN-γ and IL-17A in regulating the severity of cholangitis versus colitis ( 10 , 20 ). Together these findings indicate that the effects of CXCR3 on the autoimmune diseases were organ specific.…”

“…Mononuclear cells from liver, spleen, and MLN were isolated and stained as described ( 10 ). Colon LPL were isolated using a standardized protocol ( 21 ).…”

“…CXCR3 expression on tumor cells promotes cancer metastasis, while its expression on T cells regulates their antitumor reactivity ( 8 , 9 ). In particular, the role of CXCR3 in different autoimmune diseases has not been fully elucidated, due to the complexity of its functions and different effects of CXCR3 on various diseases ( 10 – 12 ).…”

Anti-drug Antibodies Against a Novel Humanized Anti-CD20 Antibody Impair Its Therapeutic Effect on Primary Biliary Cholangitis in Human CD20- and FcγR-Expressing Mice

“…The significance of B cell in the immunopathology of autoimmune cholangitis is well documented in patients with PBC and animal models ( 6 , 9 , 10 , 13 , 15 , 52 – 55 ). This study demonstrated that B cells promote the development of PBC-like liver disease, and partial but substantial B-cell depletion with humanized anti-hCD20 antibody (TKM-011) effectively attenuates bile duct damage in the hCD20 hFcγR-expressing dnTGF-βRII mice.…”

“…We have previously reported the use of dominant negative TGF-β receptor II (dnTGF-βRII) mice as a model for human PBC ( 12 ). The expression of dnTGF-βRII is limited to selected cell lineages including CD4 + , CD8 + , and CD1d-restricted natural killer T (NKT) cells; B cell function is normal in this model ( 12 , 13 ). We previously demonstrated that treatment of juvenile mice with a monoclonal anti-mouse CD20 antibody was effective in preventing PBC, but that responses were reduced when treatment was initiated in older mice ( 14 ).…”