Aims
Liver inflammation is a common extraintestinal manifestation of inflammatory bowel disease (IBD); however, whether liver involvement is a consequence of a primary intestinal defect or
Background and aims
Liver inflammation is a common extraintestinal manifestation of inflammatory bowel disease (IBD); however, whether liver involvement is a consequence of a primary intestinal defect or
Conclusions
Activated intrahepatic CD4+ T-cells induce liver inflammation and contribute to experimental ileitis via locally-impaired hepatic immunosuppressive function.
Methods
Liver inflammation and immune cell subsets were characterized in ileitis-prone SAMP1/YitFc (SAMP) and AKR/J (AKR) control mice, lymphocyte-depleted SAMP (SAMPxRag-1-/-), and immunodeficient SCID recipient mice receiving SAMP or AKR donor CD4+ T-cells. Proliferation and suppressive capacity of CD4+ T-effector (Teff) and T-regulatory (Treg) cells from gut-associated lymphoid tissue (GALT) and livers of SAMP and AKR mice were measured.
Results
Surprisingly, prominent inflammation was detected in 4-wk-old SAMP livers, prior to histologic evidence of ileitis, while both disease phenotypes were absent in age-matched AKRs. SAMP liver disease was characterized by abundant infiltration of lymphocytes, required for hepatic inflammation to occur, a Th1-skewed environment, and phenotypically-activated CD4+ T-cells. SAMP intrahepatic CD4+ T-cells also had the ability to induce liver and ileal inflammation when adoptively transferred into SCID recipients, whereas GALT-derived CD4+ T-cells produced milder ileitis, but not liver inflammation. Interestingly, SAMP intrahepatic CD4+ Teff cells showed increased proliferation compared to both SAMP GALT- and AKR liver-derived CD4+ Teff cells, while SAMP intrahepatic Tregs were decreased among CD4+ T-cells and impaired in in vitro suppressive function compared to AKR. Conclusions: Activated intrahepatic CD4+ T-cells induce liver inflammation and contribute to experimental ileitis via locally-impaired hepatic immunosuppressive function.