Complete differentiation of CD8+ T cells activated locally within the transplanted liver

Abstract

The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account for the persistence of liver infections, such as malaria and viral hepatitis. These phenomena have led to the hypothesis that antigen presentation within the liver is abortive, leading to T cell tolerance or apoptosis. Here we test this hypothesis in an optimized orthotopic liver transplantation model. In direct contradiction to this model, the liver itself induces full CD8+ T cell activation and differentiation. The effects of microchimerism were neutralized by bone marrow transplantation in the liver donor, and the lack of liver-derived antigen-presenting cells was documented by eight-color flow cytometry and by sensitive functional assays. We conclude that local antigen presentation cannot explain liver tolerance. On the contrary, the liver may be an excellent priming site for naive CD8+ T cells.

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

“…CTLs arising from lower-affinity interactions were also detected when inflammation triggered TLRs and costimulatory molecules that change the nature of the signals delivered by APCs to T cells (33). Third, this study explains why previous studies expressing OVA in hepatocytes have shown that OT-I T cells developed into CTLs (11,12,24). In all these studies, OT-I CTL activity was detected at week 1, before the onset of silencing observed in the present study, which was mediated by persisting liver antigen at week 3.…”

“…By identifying the relative importance of antigen level, TCR: pMHC affinity, and cross-presentation to CTL generation following activation by hepatocyte-expressed antigen, our model reconciles apparently discordant findings from several groups investigating the outcome of intrahepatic CD8 T-cell activation. First, this study ends an ongoing debate over whether T-cell tolerance observed in transgenic models is primarily a result of central tolerance or other regulatory mechanisms caused by constitutive transgene expression (11,12). 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.…”

“…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.…”

“…However, depending on the choice of antigen expressed and mode of delivery, the outcome of intrahepatic CD8 T-cell activation has been varied, ranging from deletion and/or functional silencing (8-10) to cytotoxic T lymphocyte (CTL) development (11,12). This observed diversity of T-cell fates parallels the heterogeneous outcomes of liver-immune interactions observed during hepatotropic viral infections in humans.…”

Role of interleukin-21 in HBV infection: friend or foe?

“…26,27 In fact, accumulating evidence has supported the concept of the liver as a secondary lymphoid organ, which can support the priming of classical CD4 1 and CD8 1 T-cell responses. [28][29][30][31] Although hepatic immune priming is generally considered to favor inherent tolerogenicity of the liver, [32][33][34] recent data from experimental animal models of human HBV have strongly demonstrated that age-dependent immune responses contributed to effective immune activation and antiviral immunity of the liver. 21,35 Additionally, the hepatic lymphoid structures possessed the capacity to support the differentiation and maturation of B-cell responses, as well as the priming of Tfh cells.…”