Intrahepatic Murine CD8 T-Cell Activation Associates With a Distinct Phenotype Leading to Bim-Dependent Death

Holz, Lauren E.; Benseler, Volker; Bowen, David G.; Bouillet, Philippe; Strasser, Andreas; O’Reilly, Lorraine A.; d’Avigdor, W.; Bishop, Alex; McCaughan, Geoffrey W.; Bertolino, Patrick

doi:10.1053/j.gastro.2008.05.078

Cited by 115 publications

(125 citation statements)

References 33 publications

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“…This model therefore essentially excludes the contribution of recipient crosspresentation to Des T-cell activation (13,16,17). Consistent with our previous findings in Alb-K b transgenic mice that express H-2K b only on hepatocytes (13,16,17), Des T-cell activation at 3 h after transfer into rAAV.K b -treated mice was restricted to the liver (Fig. 1G).…”

Section: T-cell Activation By Cross-presentation In Lymphoid Tissuessupporting

confidence: 90%

“…We recently described two mechanisms involved in impairing effector responses after intrahepatic activation: nonapoptotic degradation of T cells in hepatocyte lysosomes within the first day of activation ["suicidal emperipolesis" (25)] and Bimdependent apoptosis of T cells surviving suicidal emperipolesis (17). Although donor OT-I cells initially retained in the liver were efficiently deleted in mice treated with high-dose rAAV.…”

Section: Discussionmentioning

confidence: 99%

“…1B). In an alternative approach, Alb-K b mice expressing transgenic H-2K b in hepatocytes under the control of the hepatocyte-specific albumin promoter (13,16,17) were bred onto the bm1 background to generate Alb-K b .bm1 recipients. OT-I T cells that were transferred into Alb-K b .bm1 recipients treated with rAAV.mOVA were also found to be activated only within the liver (Fig.…”

Section: A Membrane Antigen Expressed By Hepatocytes Is Efficiently Cmentioning

confidence: 99%

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

Tay

Wong

McDonald

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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115

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CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions. rAAV | CTL | TCR | cytotoxicity T he liver is acknowledged to possess unique tolerogenic properties, which have likely evolved to maintain immunological unresponsiveness toward food-derived and microbial antigens that enter the circulation via the gut (1, 2). This tolerogenic capability of the liver is demonstrated in animal models of liver transplantation, in which liver allografts are accepted across complete MHC mismatch barriers and are able to protect other donor tissues from rejection (reviewed in ref.3). In humans, the tolerogenic hepatic environment is likely to contribute to impaired immune clearance of the hepatitis B virus (HBV) and hepatitis C virus (HCV), which result in persistent infection in a significant proportion of exposed individuals and are associated with major morbidity and mortality. In contrast, effective immune responses to hepatotropic pathogens leading to resolution of infection are observed in most hepatitis A and E virus infections, the majority of individuals infected with HBV during adulthood, and a minority of those infected by HCV (reviewed in refs. 4, 5). The liver is also susceptible to a variety of autoimmune-mediated conditions (6). Collectively, these observations indicate that effective immune responses can be initiated and/or sustained in the liver despite its apparent predisposition toward the generation of tolerance. Unfortunately, there is no small animal model in which to study the parameters that determine the balance between intrahepatic immunity and tolerance in viral hepatitis. Thus, the factors that shape immune outcome have not yet been identified.By studying the fate of ...

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Section: T-cell Activation By Cross-presentation In Lymphoid Tissuessupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: A Membrane Antigen Expressed By Hepatocytes Is Efficiently Cmentioning

confidence: 99%

See 1 more Smart Citation

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

Tay

Wong

McDonald

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

115

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“…Furthermore, it would be interesting to investigate other mechanisms of intrahepatic T cell tolerance induction, such as Bim-dependent T cell death. 35 Our findings may be of considerable importance in understanding immune failure in cancer patients with hyporesponsive CD8 ϩ T cells. 36 Interestingly, in some clinical situations effector function can be restored on removal of persistent antigen, 37 indicating that here, the amount of tumor antigen plays a role in determining immunological outcome.…”

Section: Discussionmentioning

confidence: 74%

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

et al. 2008

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The reason the adaptive immune system fails in advanced liver tumors is largely unclear. To address this question, we have developed a novel murine model that combines c-mycinduced autochthonous tumorigenesis with expression of a cognate antigen, ovalbumin (OVA). When c-myc/OVA transgenic mice were crossed with liver-specific inducer mice, multifocal hepatocellular carcinomas co-expressing OVA developed in a tetracycline-dependent manner with a short latency and 100% penetrance. Transferred OVA-specific T cells, although infiltrating the tumor at high numbers, were hyporesponsive, as evidenced by a lack of in vivo cytotoxicity and interferon gamma production. This allowed the tumor to progress even in the presence of large numbers of antigen-specific T cells and even after vaccination (OVA؉CpG-DNA). Interestingly, T cell receptor down-modulation was observed, which may explain antigen-specific hyporesponsiveness. This model is helpful in understanding liver cancer-specific mechanisms of T cell tolerance and dissection of antigen-specific and nonspecific mechanisms of immunotherapies in the preclinical phase. Clinical observations suggest that the immune system is important in keeping tumor growth under control. [3][4][5] However, the immune system is frequently unable to control tumor burden in patients suffering from advanced cancer arising in solid parenchymatous organs, such as the liver. One reason could be that the liver represents a tolerogenic environment for T cells. 6,7 Another reason could be that tolerance occurs because of a tolerizing microenvironment specific for advanced autochthonous tumors that arise spontaneously and slowly over time. Third, tumor antigen may be transported to lymphatic tissues for induction of cross-tolerance, which has been described as a mechanism of peripheral CD8 ϩ T cell tolerance induction against self-antigens. 8 Recent reports indicate that immune tolerance in spontaneous tumors occurs because of a failure of the adaptive immune system. 9,10 However, the mechanism of tolerance induction in autochthonous tumors remains poorly defined.Tumor antigen-specific immune responses are difficult to track, both in autochthonous tumor models and in patients, because antigens in spontaneous tumors are largely unknown or not sufficiently immunogenic. To circumvent this limitation, we generated a novel "patientlike" model of HCC, in which the adaptive T cell response can be studied. In particular, we aimed to characterize the adaptive T cell response in advanced au-

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“…Priming of naïve CD8 1 T cells in the liver usually leads to tolerance instead of immunity, accompanied by poor effector functions and apoptosis of activated CD8 1 T cells due to an increased expression of the pro-apoptotic protein Bim. 55,56 Consistently, Bim was upregulated on HBV-specific CD8 1 T cells during chronic HBV infection and contributed to the deletion of HBV-specific CD8 1 T cells. 57 LSECs are unique liver-resident antigen-presenting cells that are capable of antigen cross-presentation and induction of CD8 1 T-cell tolerance under noninflammatory conditions 58 or promotion of CD8 1 T-cell immunity under certain conditions, such as viral infection.…”

Section: Activation Of Tlr-mediated Signaling Pathways Modulates Hbv-mentioning

confidence: 83%

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhang

Yang

et al. 2014

Cell Mol Immunol

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It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T-and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

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Intrahepatic Murine CD8 T-Cell Activation Associates With a Distinct Phenotype Leading to Bim-Dependent Death

Cited by 115 publications

References 33 publications

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

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

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

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

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