The liver has the ability to prime immune responses against neo
antigens provided upon
infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as
endotoxins or food
antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreER(T2) mouse model. Upon
tamoxifen administration OVA
antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with
antigen-expressing hepatocytes, we adoptively transferred K(b)/OVA257-264-specific OT-I T cells to OVA_X_CreER(T2) mice or generated triple transgenic OVA_X CreER(T2)_X_OT-I mice. OT-I T cells become activated in OVA_X_CreER(T2) mice and induce an acute and transient
hepatitis accompanied by liver damage. In OVA_X_CreER(T2)_X_OT-I mice, OVA induction triggers an OT-I T cell mediated,
fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting
hepatitis, and recover after 9 weeks. In these experimental settings, recovery from
hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the
antigen-expressing hepatocytes. Moreover, a relapse of
hepatitis can be induced upon re-induction of cured OVA_X_CreER(T2)_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of
tamoxifen inducible tissue specific
antigen expression that reflects the heterogeneity of
viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent
antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and
antigen clearance.