Effects and regulation of autoreactive CD8+ T cells in a transgenic mouse model of autoimmune hepatitis.
OBJECTIVE
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown etiology. Autoreactive T cells are thought to mediate liver injury, but the pathogenesis of AIH is poorly understood because of the lack of suitable animal models. We established a mouse model to investigate liver-specific T-cell responses and assess the effects and regulation of autoreactive CD8(+) T cells in the pathogenesis of AIH.


METHODS
We generated transgenic mice expressing the influenza virus hemagglutinin (HA) autoantigen under control of mouse albumin regulatory elements and alpha-fetoprotein enhancers (Alb) specifically in the liver (Alb-HA mice); they were crossed with mice that express a specific T-cell receptor (TCR) (CL4-TCR). CL4-TCR transgenic CD8(+) T cells were also adoptively transferred into Alb-HA mice. We investigated immunologic mechanisms of CD8(+) T cell-induced liver damage and of counteracting peripheral tolerance.


RESULTS
The double-transgenic mice (Alb-HA/CL4-TCR) spontaneously developed chronic, autoimmune-mediated hepatitis, characterized by necroinflammatory lesions, hepatic fibrosis, and increased levels of aminotransferase; these features resembled those of AIH. Interestingly, most liver-infiltrating, HA-specific CD8(+) T cells had an anergic phenotype; regulatory CD4(+)CD25(+)Foxp3(+) T cells accumulated in the inflamed liver.


CONCLUSIONS
The continuous development of a few, HA-specific CD8(+) effector T cells is sufficient to induce chronic hepatitis. Peripheral tolerance mechanisms such as induction of T-cell anergy and accumulation of regulatory CD4(+)CD25(+)Foxp3(+) T cells protect the liver from severe damage. Our mouse model that spontaneously develops chronic autoimmune-mediated hepatitis provides a new tool to investigate autoantigen-specific T-cell responses and regulatory mechanisms involved in the prevention and pathogenesis of AIH.
Zierden
Mario
M
Institute for Pathology, University Hospital of Cologne, Cologne, Germany. mario.zierden@uni-koeln.de
Kühnen
Elisabeth
E
Odenthal
Margarete
M
Dienes
Hans-Peter
HP
D019264:Adoptive Transfer; D000418:Albumins / Q000235:genetics; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005838:Genotype; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012737:Sex Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D013997:Time Factors; D000509:alpha-Fetoproteins / Q000235:genetics
D000418:Albumins; D001324:Autoantigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011948:Receptors, Antigen, T-Cell; D000509:alpha-Fetoproteins