Liver infections with hepatotropic viruses, such as hepatitis B virus and hepatitis C virus are accompanied by viral persistence and immune failure. CD8+ T cells are crucial mediators of the intrahepatic antiviral immune response. Chronic infections of the liver and other organs correlate with T-cell exhaustion. It was previously suggested that high antigen load could result in T-cell exhaustion. We aimed at elucidating the impact of different intrahepatic antigen loads on the quality of CD8+ T-cell-mediated immunity by employing an infection-free transgenic mouse model expressing ovalbumin (Ova) as the target antigen. Adoptive transfer of OT-I cells induced a transient intrahepatic immune response toward both high and low Ova levels. However, antigen clearance was achieved only in mice expressing low antigen levels. In contrast, T cells exposed to high antigen levels underwent exhaustion and became depleted, causing antigen persistence. Moreover, when functional T cells were exposed to high intrahepatic antigen levels, a complete transition toward exhaustion was observed. Thus, this study shows that the antigen expression level in the liver correlates inversely with T-cell immunity in vivo and governs the efficiency of immune responses upon antigen presentation.

In Plasmodium falciparum malaria, CD8 + T cells play a double-edged role. Liver-stage specific CD8 + T cells can confer protection, as has been shown in several vaccine studies. Blood-stage specific CD8 + T cells, on the other hand, contribute to the development of cerebral malaria in murine models of malaria. The role of CD8 + T cells in humans during the blood-stage of P. falciparum remains unclear. As part of a cross-sectional malaria study in Ghana, granzyme B levels and CD8 + T cells phenotypes were compared in the peripheral blood of children with complicated malaria, uncomplicated malaria, afebrile but asymptomatically infected children and non-infected children. Granzyme B levels in the plasma were significantly higher in children with febrile malaria than in afebrile children. CD8 + T cells were the main T cell subset expressing granzyme B. The proportion of granzyme B + CD8 + T cells was significantly higher in children with complicated malaria than in uncomplicated malaria, whereas the activation marker CD38 on CD8 + T cells showed similar expression levels. This suggests a pathogenic role of cytotoxic CD8 + T cells in the development of malaria complications in humans.

Immune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients. Vaccination-induced endogenous CD8 T cells could eliminate low antigen loads in liver but were functionally impaired if confronted with elevated antigen loads. Strikingly, only by conditioning the liver environment with TLR9 ligand prior and early after peripheral vaccination, successful immunization against high intrahepatic antigen density with its elimination was achieved. Moreover, TLR9 immunomodulation was also indispensable for functional memory recall after high frequency antigen challenge. Together, the results indicate that TLR9-mediated conditioning of liver environment during therapeutic vaccination or antigen reoccurrence is crucial for an efficacious intrahepatic T cell response.

Abnormalities of the long arm of chromosome 6 are a common feature in various B-cell malignancies. In most cases, the genes involved have not yet been clearly identified. We have molecularly characterized the recently established Burkitt lymphoma cell line BLUE-1 that carries a t(6;20)(q15;q11.2) rearrangement in addition to the typical t(8;14) with MYC-IGH fusion. To identify the gene loci involved on both chromosomes we applied a sequential BAC clone mapping strategy. By using RT-PCR we were finally able to detect a chimeric mRNA transcript showing a fusion of the first (non-coding) exon of BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) on 6q15 to the second exon of BCL2L1 (BCL-X) on 20q11. Various fusion transcripts were detected for different BCL2L1 (BCL-XL) isoforms. The fusion ultimately results in strong expression of the BCL2L1 (BCL-XL) anti-apoptosis protein, as demonstrated by immunoblotting. This is the first report that shows the involvement of both BCL2L1 and the transcription factor BACH2 in a chromosomal rearrangement. It points to BACH2 as a possibly important target in lymphomas with 6q aberrations, although other genes on 6q are probably also involved in these cases. Moreover, it suggests that members of the BCL2 anti-apoptosis gene family other than BCL2 itself might also be involved in lymphoma.

BackgroundThe role of regulatory CD4 T cells (Treg) in immune-mediated liver disease is still under debate. It remains disputed whether Treg suppress T cell-mediated hepatitis in vivo and whether hepatic regulatory T cells are functional in patients with autoimmune hepatitis.MethodsWe used TF-OVA mice, which express ovalbumin in hepatocytes, to investigate the impact of Treg in a model of autoimmune hepatitis. Treg isolated from inflamed livers of TF-OVA mice were tested for their functionality in vitro. By employing double transgenic TF-OVAxDEREG (DEpletion of REGulatory T cells) mice we analyzed whether Treg-depletion aggravates autoimmune inflammation in the liver in vivo.ResultsCD25+Foxp3+ CD4 T cells accumulated in the liver in the course of CD8 T cell-mediated hepatitis. Treg isolated from inflamed livers were functional to suppress CD8 T-cell proliferation in vitro. Depletion of Treg in TF-OVAxDEREG mice dramatically amplified T cell-mediated hepatitis. Repeated administration of antigen-specific CD8 T cells led to a second wave of inflammation only after depletion of Treg.ConclusionOur data add to the evidence for an important role of Treg in autoimmune hepatitis and show that Treg reduce the severity of T-cell mediated hepatitis in vivo. They constitute a key immune cell population that actively maintains a tolerogenic milieu in the liver and protects the liver against repeated inflammatory challenges.