Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis

Abstract

The pathogenesis of autoimmune liver diseases is poorly understood. Animal models are necessary to investigate antigen presentation and priming of T-cells in the context of autoimmunity in the liver. Transgenic mouse models were generated in which the model antigen ovalbumin is expressed in hepatocytes (TF-OVA) or cholangiocytes (ASBT-OVA). A utoimmune hepatitis and cholangitis are triggered by autoreactive T-cells. Animal models are needed to study the early events in their pathogenesis, namely, the priming of autoreactive T-cells. The requirements for an immune-based animal model are restriction of the immune response to the liver, antigen specificity, and the potential to study the priming of CD8 and CD4 T-cells. Several animal models of autoimmune hepatitis have been developed, 1 none of which fulfills these criteria. Transgenic expression of foreign major histocompatibility complex (MHC) class I molecules in the liver has been widely used. [2][3][4] However, this model has a significant disadvantage: unlike the pathophysiology of an immune or autoimmune reaction, CD8 T cells recognize their antigen on hepatocytes but the antigen is not presented by professional antigen-presenting cells (APCs) in this model. Injection of the synthetic peptide ova p257-264 (SIINFEKL) into mice followed by transfer of antigenspecific CD8 T-cells has also been used, 5 but the possibility of peptide binding to MHC-I molecules on T-cells themselves and their activation by each other 6 or by unrelated cells is a possible concern. Infection with virus expressing ovalbumin 7 results in temporary expression of ovalbumin but also activation of innate immune mechanisms. No animal model exists that allows the simulta-

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

“…Unexpectedly, crosspresentation of liver-expressed antigen promoted the generation of CTLs ("cross-priming") and not deletional tolerance ("crosstolerance") as reported for pancreatic self-antigen (23). It is possible that low-level immunogenicity of rAAV vectors altered the quality of cross-presenting APCs in our model; however, this is unlikely to be the explanation, as OT-I T cells transferred into mice expressing transgenic OVA in a noninflammatory setting have also been reported to develop into CTL (24). Rather, we favor the possibility that efficient cross-priming was promoted by the high amount of antigen expressed by hepatocytes.…”

“…Regardless of de novo (rAAV.K b treatment in this study) or transgenic [Alb-K b mice (8,13,17,25)] expression, Des T cells activated by hepatocytes never developed into CTL, a finding similarly observed for OT-I T cells activated intrahepatically by de novo-expressed loweraffinity ligands. Overall, a wide variety of outcomes have been reported after intrahepatic CD8 T-cell activation in mice expressing transgenic liver antigens, including ignorance (33), deletional tolerance (8,13,17,25), and partial or full effector differentiation (11,12,24,34). These variable outcomes are likely caused by the different TCR:pMHC affinity and/or levels of antigen expression in these models.…”

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation #

“…Interestingly, in transgenic mouse models with OVA expression in normal hepatocytes, 25 OVA-specific CD8ϩ T cells cause autoimmune hepatitis, not tolerance. In our model, we could not use serum alanine aminotransferase as a measurement of liver cell injury, because this parameter was elevated because of tumor growth.…”

“…Although other parameters such as administration of CD4ϩ OVA-specific T cells or CD1d-restricted invariant natural killer T cells 26 still need to be tested in our model, OVA-specific T cells in c-myc OVA tgϩ tumor-bearing mice do not induce overt bystander autoimmune hepatitis. Interestingly, when OVA is expressed in normal hepatocytes, 25 OT I T cells proliferate in the liver and the spleen in a time-delayed fashion, suggesting priming of CD8ϩ T cells in the liver and redistribution to the spleen. This is in contrast to our tumor model, where priming apparently occurs at the same time in the liver and in secondary immune organs based on activation and proliferation kinetics.…”

Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

“…To determine whether antigen-dependent mechanisms of injury are relevant to hepatic I/R injury, we employed OT-II mice. These mice have CD4 ϩ T cells that express a TCR that only recognizes ovalbumin (7). Hepatic I/R injury was attenuated in OT-II mice after both 4 and 8 h of reperfusion, as measured by serum ALT levels, compared with wild-type mice (Fig.…”