CD4+ intrahepatic lymphocytes drive liver inflammation via impaired regulatory pathways in a murine model of Crohn’s-like ileitis

Crosstalk between the liver and intestines represents an important pathophysiological interface in inflammatory bowel disease (IBD), a disorder associated with significant hepatobiliary manifestations; however, whether liver involvement is a consequence of a primary intestinal defect or the result of a concomitant disease process remains unclear. Liver inflammation was evaluated in ileitis-prone SAMP1/YitFc (SAMP) and control AKR mice, reciprocal SAMP/AKR bone marrow chimeras (BMC), lymphocyte-depleted SAMP (SAMPXRAG-2 KO), and immunodeficient SCID mice receiving SAMP or AKR donor CD4+ cells. Isolated non-parenchymal liver cells (NPLC) were characterized by flow cytometry and by quantitative (q)PCR to assess cytokine production. BMC revealed that, unlike SAMP ileitis that originates from a non-hematopoietic source, both non-hematopoietic and hematopoietic compartments are needed for liver inflammation to occur; in fact, SAMPXRAG-2 KO mice displayed no hepatic inflammation, confirming a requirement for lymphocytes. Indeed, SAMP intrahepatic infiltrates consisted of a predominant Th1-polarized CD4+ population that caused severe liver and ileal inflammation when adoptively transferred into SCID recipients. Conversely, gut-associated lymphoid tissue (GALT)-derived CD4+ T-cells produced ileitis, but not liver inflammation. Interestingly, decreased frequencies of resident tolerogenic populations, i.e. liver sinusoidal endothelial cells (LSEC) and regulatory T-cells (Treg), and impaired in vitro suppressive function of Treg, were evident in SAMP vs. AKR livers. These results challenge the current paradigm that IBD-associated liver inflammation is a consequential secondary event and suggest that intrahepatic CD4+ T-cells acquire pathogenic potential in predisposed individuals, through altered regulatory mechanisms within the host liver.