Dysregulated Intrahepatic CD4+ T-Cell Activation Drives Liver Inflammation in Ileitis-Prone SAMP1/YitFc Mice

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 results from alternative pathogenic processes remains unclear. Therefore, we sought to determine the potential pathogenic mechanism(s) of concomitant liver inflammation in an established murine model of IBD. 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.