Hepatic T Cell Tolerance Induction in An Inflammatory Environment

Abstract

For the development of autoimmune hepatitis (AIH), genetic predisposition and environmental triggers are of major importance. Although experimental AIH can be induced in genetically susceptible mice, the low precursor frequency of autoreactive T cells hampers a deeper analysis of liver-specific T cells. Here, we established a system where the model antigen hemagglutinin (HA) is expressed exclusively in hepatocytes of Rosa26-HA mice following administration of a replication deficient adenovirus expressing Cre recombinase (Ad-Cre). Under these conditions, hepatocytes mimic the generation of altered-self neoantigens. To follow autoreactive T cells during AIH, we adoptively transferred HA-­specific Cl4-TCR and 6.5-TCR T cells into Ad-Cre infected ­Rosa26-HA mice. Alternatively, Rosa26-HA mice have been crossed with TCR transgenic mice that were infected with Ad-Cre to break hepatic tolerance and induce the expression of the HA antigen as a hepatic self-antigen. Surprisingly, neither adoptive transfer nor a very high precursor frequency of autoreactive T cells was able to break tolerance in the context of adenoviral infection. The low proliferation of the antigen experienced autoreactive T cells despite the presence of the autoantigen and inflammation points to anergy as a potential tolerance mechanism. This model underscores the crucial importance of genetic susceptibility to break tolerance against hepatic autoantigens.

Autoimmune hepatitis induction can occur in the liver

“…Because T cells were identified as the definitive drivers of emAIH, it is noteworthy that there was a reduced number of intrahepatic T cells (Figure A). The relative and absolute number of B cells increased after splenectomy (Figure B), but the IgG serum level did not change (data not shown).…”

“…Because T cells were identified as the definitive drivers of emAIH, 6,8 it is noteworthy that there was a reduced number of F I G U R E 1 Splenectomy does not impact the development of emAIH. A, Splenectomized (black dots) or nonsplenectomized NOD/Ltj mice (black squares) received 4 × 10 9 Ad-FTCD particles.…”

PD-1/CTLA-4 Blockade Leads to Expansion of CD8+PD-1int TILs and Results in Tumor Remission in Experimental Liver Cancer

“…Tumors were induced in 6- to 8-week-old BALB/cJHanZtm mice. HA-specific T cells were obtained from congenic CD45.1 + BALB-Ptprca-Tg(TCR/C-TCR(HA/PR8/34))CL4/Rlf mice [ 8 ]. Albumin-cre x Rosa-26HA F1 mice were utilized for the generation of liver tumor cells.…”

“…Liver tumor cells expressing the influenza hemagglutinin HA peptide were generated by inducing autochthonous liver tumors in Albumin-cre x Rosa-26HA F1 mice [ 8 ] by hydrodynamic cotransfection [ 9 ] of plasmids carrying oncogenes and Sleeping Beauty transposase (pPGK SB13 Kras g12V and pT/p53-246 sh p53). Under these conditions, HA is expressed at endogenous levels (see online suppl.…”

Splenectomy induces biochemical remission and regeneration in experimental murine autoimmune hepatitis

“…Paraffin-embedded sections (5 µm) were prepared for hematoxylin and eosin (HE) staining and analyzed with an AxioImagerM1 using AxioVision 4.8 software (Zeiss). The sections were further examined in a blinded manner by a pathologist using the approved modified hepatitis activity index (mHAI) for autoimmune hepatitis as described previously [ 5 , 21 ]. Immunofluorescence microscopy was performed as previously described [ 11 – 13 ].…”