LAUSR

The liver participates in a multitude of metabolic functions that are critical for sustaining human life. Despite constant encounters with antigenic‐rich intestinal blood, oxidative stress, and metabolic intermediates, there is no appreciable immune response. Interestingly, patients undergoing orthotopic liver transplantation benefit from a high rate of graft acceptance in comparison to other solid organ transplant recipients. In fact, cotransplantation of a donor liver in tandem with a rejection‐prone graft increases the likelihood of graft acceptance. A variety of players may account for this phenomenon including the interaction of intrahepatic antigen‐presenting cells with CD4+ T cells and the preferential induction of forkhead box P3 (Foxp3) expression on CD4+ T cells following injurious stimuli. Ineffective insult management can cause chronic liver disease, which manifests systemically as the following: antibody‐mediated disorders, ineffective antiviral and antibacterial immunity, and gastrointestinal disorders. These sequelae sharing the requirement of CD4+ T cell help to coordinate aberrant immune responses. In this review, we will focus on CD4+ T cell help due to the shared requirements in hepatic tolerance and coordination of extrahepatic immune responses. Overall, intrahepatic deviations from steady state can have deleterious systemic immune outcomes and highlight the liver's remarkable capacity to maintain a balance between tolerance and inflammatory response while simultaneously being inundated with a panoply of antigenic stimuli. Liver Transplantation 24 89–97 2018 AASLD.